RU2804702C2 - Modified lipidated relaxin b-chain peptides and their therapeutic use - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention can be used in medical practice. The invention discloses a biologically active single-chain relaxin peptide, which is characterized by the following formula (I): Ac-X₁₀-E-G-R-E-X₁₅-V-R-X₁₈-X₁₉-I-X₂₁-X₂₂-E-G-X₂₅-S-X₂₇-X₂₈-X₂₉-X₃₀-X₃₁-X₃₂-X₃₃-NH₂.

EFFECT: invention has agonist activity against the relaxin receptor (RXFP1) and can be used to obtain a medicinal product for the treatment of various cardiovascular diseases associated with dysfunction and disturbances in RXFP1 activation.

28 cl, 6 ex, 9 tbl, 2 dwg

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to peptide analogs of the relaxin-2 B chain capable of activating the RXFP1 receptor.

In particular, the present invention relates to lipidated peptide analogues of the relaxin-2 B chain capable of activating the RXFP1 receptor.

In addition, the present invention provides pharmaceutical compositions containing at least the specified peptides and the peptide or a pharmaceutical composition based thereon in accordance with the present invention, for use as a medicinal product and, in particular, for use in the treatment and/or prevention of various diseases or conditions associated with the RXFP1 receptor, more particularly diseases or conditions selected from

- group consisting of fibrosis; fibrotic diseases, in particular systemic sclerosis, scleroderma and fibromyalgia; idiopathic pulmonary fibrosis; kidney diseases associated with fibrosis; pulmonary hypertension and preeclampsia;

- the group consisting of diseases of the heart and blood vessels, in particular the group consisting of acute or chronic heart failure, systolic or diastolic heart failure, coronary heart disease, atherosclerosis, microvascular angina and cardiovascular complications of diabetes; and/or

- a group consisting of types of renal failure, in particular renal dysfunction in cirrhosis; chronic renal failure and acute renal failure.

PREREQUISITES FOR CREATION OF THE INVENTION

Human relaxin-2 (relaxin H2) is a 6 kDa peptide hormone consisting of 53 amino acids. Its structure consists of two separate polypeptide chains, i.e. relaxin H2 chain A (SEQ ID NO: 100) and relaxin H2 chain B (SEQ ID NO: 101), linked by two disulfide (S-S) bonds, with a third intrachain S-S bond , located in circuit A, as follows.

Chain A of relaxin H2: H-Gln-Leu-Tyr-Ser-Ala-Leu-Ala-Asn-Lys-Cys*-Cys**-His-Val-Gly-Cys*-Thr-Lys-Arg-Ser-Leu -Ala-Arg-Phe-Cys***-OH (SEQ ID NO: 100)

Relaxin H2 chain B: H-Asp-Ser-Trp-Met-Glu-Glu-Val-Ile-Lys-Leu-Cys**-Gly-Arg-Glu-Leu-Val-Arg-Ala-Gln-Ile-Ala -Ile-Cys***-Gly-Met-Ser-Thr-Trp-Ser-OH (SEQ ID NO: 101),

where Cys*, Cys** and Cys*** denote disulfide bonds between cysteine residues with the same marks.

Relaxin-2 is a naturally occurring peptide hormone produced by the corpus luteum with peak levels in a woman's circulation during the first trimester of pregnancy. Relaxin-2 belongs to the insulin-like peptide family, whose members exhibit multiple effects upon binding to different types of receptors classified as relaxin family peptide (RXFP) receptors (RXFP1, RXFP2, RXFP3, and RXFP4).

RXFP1 is the main relaxin receptor. RXFP1 contains a large extracellular domain with a single low-density lipoprotein receptor class A (LDLa) module at the amino terminus and 10 extracellular leucine-rich repeat (LRR) domains followed by 7 transmembrane (7TM) coiled-coil domains. The LDLa module of RXFP1 is attached to the LRR domain via a 32-residue linker.

Activation of RXFP1 is a complex multistep process. Previous studies have shown that Arg13, Arg17 and Ile20 from the arginine cassette (RxxxRxxI/V, where x is any residue) of the relaxin H2 B chain bind to Asp231, Asp279, Glu233 and Glu277 located on LRR4-8 of the LRR domain of RXFP1. Ligand binding alone is not sufficient to activate the receptor. Truncation or replacement of the LDLa module results in an inactive receptor despite binding to the extracellular domain. A study (Bruell, S. et al ., Front. Endocrinol. (Lausanne) 4, 171 (2013)) involving replacement of the LDLa modules RXFP1 and RXFP2 highlighted the role of the linker in receptor activation. The LRR (high affinity site) and first exo-loops (low affinity sites) of the transmembrane domains are involved in binding to relaxin, while the LDLa module is required for receptor activation via exo-loop 2 (Sethi A. et al . Nature Communications ( 2016)).

In some species, relaxin can also activate RXFP2, the native leucine-rich repeat-containing GPCR for insulin-like peptide 3 (INSL3). This suggests that potential cross-reactivity may be due to different biological effects of relaxin, although there is currently no evidence for a physiological role for relaxin acting solely through RXFP2.

Recently published data showed that there are interspecies differences in the ability of agonists to activate RXFP1, with a specific difference in the ECL3 domain between humans and rodents (Huang et al. Frontiers in Endocrinology 2015 Aug 17;6:128). In parallel, biased agonist activity has been described for some relaxin-derived single-chain mimetics (Hossain et al. Chem. Sci., 2016, 7, 3805). However, based on the IUPHAR nomenclature, RXFP1 is a Gs-coupled receptor, and the primary signaling pathway of RXFP1 leads to the accumulation of cAMP (cyclic adenosine monophosphate).

Relaxin was first identified as a pregnancy hormone involved not only in uterine remodeling and embryo implantation, but also in the hemodynamic adaptation of pregnant women. These adaptations include decreased vascular resistance, increased cardiac output, and increased GFR, a combination of effects aimed at reducing cardiac afterload. These properties have led to the use of recombinant human relaxin 2 in several clinical trials in the context of acute heart failure.

The beneficial cardiovascular effects of relaxin, which are associated with changes in the renal and systemic vasculature, have also been demonstrated in patients with congestive and acute heart failure in preclinical studies and phase II clinical trials. In awake normotensive and hypertensive male and female rats, acute intravenous and chronic subcutaneous administration of relaxin increases cardiac output and global vascular compliance and reduces systemic vascular resistance without affecting mean arterial pressure.

Relaxin has also been shown to reduce mean arterial pressure in a rat model of hypertension. The vascular effects of relaxin extend to the modification of passive wall compliance. Chronic subcutaneous infusion of relaxin in rats and mice increases vascular compliance in the small renal, mesenteric, uterine, and carotid arteries. In addition, relaxin has been shown to have antifibrotic properties in animal models of cardiac and renal fibrosis.

Thus, relaxin may be useful in patients with chronic heart failure by reducing afterload and facilitating cardiac function, as well as in patients with pulmonary hypertension, in heart failure with reduced or preserved ejection fraction, and in patients with fibrotic diseases, including systemic sclerosis, idiopathic pulmonary fibrosis and any kidney disease including fibrosis.

Thus, relaxin-2 is of great therapeutic interest.

However, the complex heterodimeric structure of relaxin H2 makes its chemical synthesis and purification difficult, resulting in low yields of the final product (Curr. Opin. Chem. Biol. 2014, 22, 47-55).

Accordingly, there is interest in producing stable relaxin peptides that have the ability of relaxin to activate RXFP1 receptors, and more specifically, peptides that retain the biological activity of relaxin while being structurally simpler than native relaxin.

Peptides with simpler structures may require less complex and more efficient synthesis than relaxin H2. This reduces the cost of treatment associated with the synthesis of relaxin H2.

Additionally, due to their simpler and smaller structure, such peptides may exhibit improved uptake compared to native relaxin, resulting in improved therapeutic activity in vivo .

Several simplified relaxin H2 analogues have been described in the literature. M.A. Hossain et al. (J. Biol. Chem. (2011), 43, 3755) identified the minimal structure of relaxin H2, showing that its B chain can be truncated to 6 or 7 amino acids at the N terminus with minimal loss of activity. The structures described in this publication are double-stranded relaxin analogues that are still difficult to synthesize and do not provide any advantage over native relaxin H2.

Further attempts have been made to simplify the relaxin family peptides. Recently in M.A. Hossain et al. In Chem. Sci. (2016),7, 3805-3819 and WO2015/157829 proposed RXFP1 agonist peptides that contain only the H2 relaxin B chain. However, as shown in this text, the peptides from WO2015/157829 have insufficient ability to activate the RXFP1 receptor.

Thus, there is a need for new peptide analogs of the relaxin-2 B chain capable of activating the RXFP1 receptor, in particular, having an improved ability to activate the RXFP1 receptor.

There is also a need for new modified relaxin peptides that have a simple structure, in particular a simpler structure than already known relaxin peptides, and have an improved ability to activate the RXFP1 receptor.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is aimed at meeting the above needs.

The present inventors do provide new modified relaxin peptides, and in particular lipidated peptides, demonstrating significantly improved ability to activate the RXFP1 receptor compared to the first simplified relaxin family peptides proposed in the prior art, as demonstrated in the following examples.

As described later herein, the present inventors have made several deletions and modifications to the native amino acid sequence of the relaxin B chain, resulting in shorter peptides having improved properties compared to native relaxin and relaxin peptides already proposed in the prior art. . In particular, the accompanying experiments demonstrate that while peptide B7-33 C11.23S (SEQ ID NO: 102) and a similar peptide from WO2015/157829, AcB7-33 C11.23S (SEQ ID NO: 103) and KKKK ( AcB7-29 C11.23S) (SEQ ID NO: 104) have a 50% activation concentration (EC ₅₀ ) of RXFP1 of 1641 nM, 929 nM and 206 nM, respectively, in the cell assay used to select the peptides of the present invention, EC values ₅₀ obtained with the lipidated peptides of the present invention are in the range from 36.4 nM to 0.07 nM. Moreover, most of the test peptides of the present invention have an EC ₅₀ value of 5 nM or less.

Moreover, although the prior art below suggests that the relaxin B chain cannot be truncated by more than 7 amino acids (J. Biol. Chem. (2011), 43, 3755; WO2015/157829) without significantly reducing activity, the peptides of the present invention are truncated by 9 amino acids at the N-terminus (Nter) and still exhibit high activity against the RXFP1 receptor.

Compared to the RXFP1 agonist peptides of WO2015/157829, the peptides of the present invention exhibit improved solubility at pH 4.5 or pH 7.5, improved stability values in plasma or rat and human blood, and in vivo half-life.

These properties will allow the peptides of the present invention to be formulated in wide concentration ranges for drug use, which will maintain their effectiveness in vivo over a longer period of time, allowing for, for example, once daily administration by the intravenous or subcutaneous route.

Accordingly, one aspect of the present invention relates to a peptide characterized by the following formula (I):

N _ter -Ac-X ₁₀ -EGREX ₁₅ -VRX ₁₈ -X ₁₉ -IX ₂₁ -X ₂₂ -EGX 25 -SX ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -X ₃₁ -X ₃₂ -X _{33 -NH 2} - _Cter ,

Where

N _ter represents the N-terminal region of the peptide;

C _ter represents the C-terminal region of the peptide;

Ac represents an acetyl group;

X ₁₀ is an amino acid selected from the group consisting of leucine, 2-aminoisobutyric acid (Aib), Nε-acetyllysine (K(Ac)) and α-methylleucine (Mel);

E represents glutamic acid (Glu);

G represents glycine (Gly);

R represents arginine (Arg);

X ₁₅ is an amino acid selected from the group consisting of lysine (Lys), arginine (Arg), homolysine (Hly), homoarginine (Har), ornithine (Orn), glutamine (Gln), phenylalanine (Phe) and leucine (Leu );

V represents valine (Val);

X ₁₈ is an amino acid selected from the group consisting of alanine (Ala), 2-aminoisobutyric acid (Aib), leucine (Leu), Nε-acetyllysine (K(Ac)) and glutamine (Gln);

X ₁₉ is an amino acid selected from the group consisting of lysine (Lys), Nε-acetyl-lysine (K(Ac)), citrulline (Cit), glutamine (Gln), alanine (Ala) and 2-aminoisobutyric acid (Aib);

I is isoleucine (Ile);

X ₂₁ is an amino acid selected from the group consisting of 2-aminoisobutyric acid (Aib) and alanine (Ala);

X ₂₂ is an amino acid selected from the group consisting of 2-aminoisobutyric acid (Aib) and isoleucine (Ile);

X ₂₅ has the following structure:

wherein

-* represents a covalent bond with the glycine preceding X ₂₅ in formula (I);

- represents a covalent bond with the serine following X ₂₅ in formula (I); And

Z represents a group of formula (II):

-[(PEGxx) _b (gE) _c C _d ],

b and c are independently equal to 1, 2, 3, 4 or 5;

PEGxx is independently a polyethylene glycol derivative selected from the group consisting of PEG ₂ , PEG ₂ DGA and TTDS;

gE is gamma-glutamic acid; And

_Cd represents a linear saturated C ₁₂ -C ₂₂ acyl group;

S represents serine (Ser);

X ₂₇ is an amino acid selected from the group consisting of threonine (Thr), lysine (Lys), arginine (Arg) and glutamine (Gln);

X ₂₈ is an amino acid selected from the group consisting of tryptophan (Trp), phenylalanine (Phe), 5-fluorotryptophan (Trp(5F)), 5-chlorotryptophan (Trp(5Cl)),

5-methoxytryptophan (Trp(5OMe)), tyrosine (Tyr), 4-fluorophenylalanine (Pfp),

1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), α-methyltryptophan (Mtr), α-methylphenylalanine (Mph), and 5-hydroxytryptophan (Wox);

X ₂₉ is an amino acid selected from the group consisting of serine (Ser), D-serine (Dser), 2-aminoisobutyric acid (Aib), threonine (Thr), α-methylserine (Mse), Nε-acetyllysine (K( Ac)) and valine (Val);

X ₃₀ is an amino acid selected from the group consisting of 2-aminoisobutyric acid (Aib), α-methyllysine (Mly), D-lysine (Dlys), lysine, homolysine (Hly), ornithine (Orn), arginine (Arg) and α-methylarginine (Mar);

X ₃₁ is an amino acid selected from the group consisting of arginine (Arg), Nω-methylarginine (Rme), alanine (Ala), Nω,Nω'-dimethylarginine (Rds, symmetrical dimethylarginine) and citrulline (Cit);

X ₃₂ is an amino acid selected from the group consisting of lysine (Lys), alanine (Ala), arginine (Arg), Nε-acetyllysine (K(Ac)) and Nε,Nε,Nε-trimethyllysine (Tml); And

X ₃₃ is an amino acid selected from lysine (Lys), Nε-acetyllysine (K(Ac)), leucine (Leu), arginine (Arg) and alanine (Ala);

or a salt or solvate thereof.

In a specific embodiment, the present invention provides a peptide characterized by formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide is capable of activating the RXFP1 receptor.

Another aspect of the present invention is a pharmaceutical composition containing at least one peptide of the present invention or a pharmaceutically acceptable salt or solvate thereof together with at least one pharmaceutically acceptable carrier.

Another aspect of the present invention relates to the peptide of the present invention, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition based thereon of the present invention for use as a drug.

Accordingly, the present invention further relates to a peptide of the present invention, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof of the present invention for use in the treatment and/or prevention of various diseases or conditions associated with the RXFP1 receptor, more particularly diseases or conditions , selected from

- group consisting of fibrosis; fibrotic diseases, in particular systemic sclerosis, scleroderma and fibromyalgia; idiopathic pulmonary fibrosis; kidney diseases associated with fibrosis; pulmonary hypertension and preeclampsia;

- the group consisting of diseases of the heart and blood vessels, in particular the group consisting of acute or chronic heart failure, systolic or diastolic heart failure, coronary heart disease, atherosclerosis, microvascular angina and cardiovascular complications of diabetes; and/or

- a group consisting of types of renal failure, in particular renal dysfunction in cirrhosis, chronic renal failure and acute renal failure.

In one embodiment, said disease or condition may be selected from the group consisting of diseases of the heart and blood vessels, in particular the group consisting of acute or chronic heart failure, systolic or diastolic heart failure, coronary artery disease, atherosclerosis, microvascular angina and cardiac -vascular complications of diabetes.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The following is presented in this context.

- "X _y " used in the formulas of the present invention, where the letter y has various meanings, represents the amino acid defined in the definition of said formulas. y indicates the position of the indicated amino acid in the native B chain of relaxin-2. For example, X ₁₀ is the amino acid at position 10 of the native relaxin-2 B chain amino acid sequence.

- “Pharmaceutically acceptable carrier” means a liquid, in particular a liquid containing the peptide of the present invention, such that the pharmaceutical composition is physiologically tolerable, i.e., can be administered to the body of an individual without causing toxicity or undue discomfort.

- The "biologically active" peptide of the present invention is a peptide capable of activating the RXFP1 receptor.

- When applicable, the amino acids in the peptides of the present invention may independently be L-amino acids or D-amino acids. In a specific embodiment, the amino acids of the present invention are L-amino acids. In this text, unless information is provided regarding the L- or D-form of a given amino acid, then the amino acid is an L-amino acid.

- N _ter and C _ter are traditional marks used to indicate, respectively,

The N-terminal region of the peptide and the C-terminal region of the peptide of the present invention.

- “Peptide” or “relaxin peptide” according to the present invention is a modified lipidated relaxin B chain peptide according to the present invention. In particular, such “peptide” or “relaxin peptide” means a peptide that is biologically active, i.e., exhibits biological activity typically associated with relaxin, and which, in particular, as stated above herein, is capable of activating the RXFP1 receptor . The level of such relaxin biological activity exhibited by the modified peptides of the present invention may be equivalent to or advantageously increased compared to the activity of naturally occurring or native relaxin or even compared to already disclosed relaxin peptides different from that of the present invention.

- The term “native” as used in this text in relation to relaxin refers to naturally occurring or wild-type molecules.

- “Prevention” means reducing the risk of occurrence of the phenomenon in question. This reduction may be complete or partial, i.e. it results in a degree of risk that is lower than that which existed before use in accordance with the present invention.

- “Treatment” means the reduction or even elimination of the undesirable condition or disease in question.

- “Individual” or “patient” means a human or non-human mammal affected or likely to be affected by a condition contemplated by the present invention. Said individual is, in particular, a human.

The present inventors have developed new modified peptides, in particular lipidated peptides.

The inventors of the present invention have unexpectedly discovered herein that the shorter and highly modified peptide of the present invention, i.e., the amino acid sequence of the present invention, has superior biological activity, in particular superior ability to activate the RXFP1 receptor compared to single B- relaxin chain known from the prior art.

Peptides of the present invention

The peptides of the present invention are characterized in that they are characterized by formula (I):

N _ter -Ac-X ₁₀ -EGREX ₁₅ -VRX ₁₈ -X ₁₉ -IX ₂₁ -X ₂₂ -EGX 25 -SX ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -X ₃₁ -X ₃₂ -X _{33 -NH 2} - _Cter ,

Where

N _ter represents the N-terminal region of the peptide;

C _ter represents the C-terminal region of the peptide;

Ac represents an acetyl group;

X ₁₀ is an amino acid selected from the group consisting of leucine, 2-aminoisobutyric acid, Nε-acetyllysine and α-methylleucine;

E represents glutamic acid;

G represents glycine;

R represents arginine;

X ₁₅ is an amino acid selected from the group consisting of lysine, arginine, homolysine, homoarginine, ornithine, glutamine, phenylalanine and leucine;

V represents valine;

X ₁₈ is an amino acid selected from the group consisting of alanine, 2-aminoisobutyric acid, leucine, Nε-acetyllysine and glutamine;

X ₁₉ is an amino acid selected from the group consisting of lysine, Nε-acetyl-lysine, citrulline, glutamine, alanine and 2-aminoisobutyric acid;

I is isoleucine;

X ₂₁ is an amino acid selected from the group consisting of 2-aminoisobutyric acid and alanine;

X ₂₂ is an amino acid selected from the group consisting of 2-aminoisobutyric acid and isoleucine;

X ₂₅ has the following structure:

wherein

-* represents a covalent bond with the glycine preceding X ₂₅ in formula (I);

- represents a covalent bond with the serine following X ₂₅ in formula (I); And

Z represents a group of formula (II):

-[(PEGxx) _b (gE) _c C _d ],

b and c are independently equal to 1, 2, 3, 4 or 5;

PEGxx is independently a polyethylene glycol derivative selected from the group consisting of PEG ₂ , PEG ₂ DGA and TTDS;

gE is gamma-glutamic acid; And

_Cd represents a linear saturated C ₁₂ -C ₂₂ acyl group;

S represents serine;

X ₂₇ is an amino acid selected from the group consisting of threonine, lysine, arginine and glutamine;

X ₂₈ is an amino acid selected from the group consisting of tryptophan, phenylalanine, 5-fluorotryptophan, 5-chlorotryptophan, 5-methoxytryptophan, tyrosine, 4-fluorophenylalanine, 1-naphthylalanine, 2-naphthylalanine, α-methyltryptophan,

α-methylphenylalanine and 5-hydroxytryptophan;

X ₂₉ is an amino acid selected from the group consisting of serine, D-serine,

2-aminoisobutyric acid, threonine, α-methylserine, Nε-acetyllysine and valine;

X ₃₀ is an amino acid selected from the group consisting of 2-aminoisobutyric acid, α-methyllysine, D-lysine, lysine, homolysine, ornithine, arginine and α-methylarginine;

X ₃₁ is an amino acid selected from the group consisting of arginine, Nω-methylarginine, alanine, Nω,Nω'-dimethylarginine and citrulline;

X ₃₂ is an amino acid selected from the group consisting of lysine, alanine, arginine, Nε-acetyllysine and Nε,Nε,Nε-trimethyllysine;

X ₃₃ is an amino acid selected from lysine, Nε-acetyllysine, leucine, arginine and alanine;

or a salt or solvate thereof.

The present invention also includes salts of peptides of formula (I) or (Ia) as defined herein, in one embodiment, pharmaceutically acceptable salts, such as acid addition salts formed by reaction with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, perchloric acid, thiocyanic acid and boric acid; or with organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid benzenesulfonic acid, p-toluenesulfonic acid, naphthalene sulfonic acid and sulfanilic acid; and salts formed by reaction with metals such as alkali metals such as sodium, potassium, lithium, zinc and aluminum.

In one embodiment, the peptide salts are pharmaceutically acceptable salts, such as acid addition salts formed by reaction with hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene sulfonic acid and sulfanilic acid; and salts formed by reaction with metals such as alkali metals such as sodium, potassium, lithium and zinc.

The present invention also includes solvates, in one embodiment, pharmaceutically acceptable solvates of the peptides of formulas (I) or (Ia) above.

Solvates mean complexes of the compounds of the present invention or their salts with solvent molecules, for example, organic solvent and/or water molecules.

According to an embodiment of the present invention, the present invention also includes a pharmaceutically acceptable salt or solvate of the peptides of the present invention.

As shown, the peptide of the present invention is an amino acid sequence.

In accordance with standard polypeptide nomenclature (J. Biol. Chem., 243:3552-59 (1969)), the abbreviations for α-amino acid residues used in the present invention are as follows.

Single letter code Three letter code Amino acid A Ala Alanin C Cys Cysteine D Asp Aspartic acid or aspartate E Glu Glutamic acid or glutamate F Phe Phenylalanine G Gly Glycine H His Histidine I Ile Isoleucine K Lys Lysine L Leu Leucine M Met Methionine N Asn Asparagine P Pro Proline Q Gln Glutamine R Arg Arginine S Ser Serin T Thr Threonine V Val Valin W Trp Tryptophan Y Tyr Tyrosine

The following abbreviations are used for unnatural or modified amino acids.

Aib 2-Aminoisobutyric acid Cit Citrulline Dser D-Serine Dlys D-Lysine Har Homoarginine Hly Homolysin Hph Homophenylalanine gE γ-Glutamic acid (glutamic acid with a carboxyl functional group attached at the γ position) Nle Norleucine, 2-aminohexanoic acid K(Ac) Nε-Acetyl-lysine, 2-amino-4-acetamidohexanoic acid Mar α-Methylarginine Mel α-Methylleucine Mly α-Methyllysine Mph α-Methylphenylalanine Mse α-Methylserine Mtr α-Methyltryptophan 1-Nal 1-Naphthylalanine 2-Nal 2-Naphthylalanine Orn Ornithine Pfp 4-Fluorophenylalanine Rds Nω,Nω'-Dimethylarginine (symmetric) Rme Nω-Methylarginine Tml Nε,Nε,Nε-Trimethyllysine Trp(5-Cl) or Trp(5Cl) 5-Chlorotryptophan Trp(5-F) or Trp(5F) 5-Fluorotryptophan Trp(5-OMe) or Trp(5OMe) 5-Methoxytryptophan Wox 5-Hydroxytryptophan

In all formulas according to the present invention, where the amino acid sequence is represented using the above abbreviations and representations using X _y such as, for example, X ₁₈ , the left and right orientation is in the traditional direction from the amino terminus to the carboxy terminus.

Accordingly, for example, if X ₂₈ is an amino acid selected from the group of tryptophan, 5-fluorotryptophan, 5-chlorotryptophan, 5-methoxytryptophan, tyrosine, phenylalanine, 4-fluorophenylalanine, 1-naphthylalanine, 2-naphthylalanine,

α-methyltryptophan, α-methylphenylalanine and 5-hydroxytryptophan, the N-terminus or amino group of said amino acid is linked to the amino acid represented by X ₂₇ and the C-terminus or carboxyl group of said amino acid is linked to the amino acid represented by X ₂₉ .

In its N-terminal (N _ter ) region, the peptide of the present invention is replaced by an acetyl group (Ac): CH ₃ C(O)-.

In its C-terminal (C _ter ) region, the peptide of the present invention is replaced by a -NH ₂ group.

At its _X25 position, the peptide of the present invention has the following structure:

This structure corresponds to the amino acid lysine, where

- the alpha (α)-nitrogen atom (*) is linked to the previous part of the peptide, i.e. to the group on N _ter X ₂₅ based on the N _ter -C _ter orientation represented in the formulas according to the present invention, through a covalent bond, in particular through a peptide bond, i.e. with glycine at position 24 (X ₂₄ );

- carbon atom of the carboxyl group ( ) is linked to the part of the peptide following the X ₂₅ position, i.e. to the group on C _ter X ₂₅ based on the N _ter -C _ter orientation represented in the formulas according to the present invention, through a covalent bond, in particular through a peptide bond, i.e. i.e. with serine at position 26 (X ₂₆ ); And

- the nitrogen atom of its side chain is connected to the Z group.

This group Z is defined as being characterized by formula (II):

-[(PEGxx) _b (gE) _c C _d ].

In formula (II), "-" represents a covalent bond to the side chain nitrogen atom of the lysine structure in X ₂₅ .

b and c are independently equal to 1, 2, 3, 4 or 5, preferably 2, 3, 4 or 5.

In a particular embodiment, b is equal to 2, 3, 4, or 5.

In a particular embodiment, c is equal to 2, 3, or 4.

In a preferred embodiment, b is equal to 2, 3, 4 or 5, and c is independently equal to 2, 3 or 4.

PEGxx in the formulas of the present invention is independently a polyethylene glycol derivative selected from the group consisting of PEG₂, P.E.G.₂DGA and TTDS.

These groups are defined as follows:

Reduction Structure IUPAC name PEG ₂ 2-[2-(2-Aminoethoxy)ethoxy]acetyl PEG ₂ DGA 2-[2-[3-[2-[2-(3-Aminopropoxy)ethoxy]ethoxy]propylamino]-2-oxoethoxy]acetyl TTDS 4-[3-[2-[2-(3-Aminopropoxy)ethoxy]ethoxy]propylamino]-4-oxobutanoyl

where in (PEGxx) _b formulas (II) represents a covalent bond to the (gE) _c group, and is a covalent bond linking a group of formula (II) to the side chain nitrogen atom of the lysine structure in X ₂₅ .

In a specific embodiment, (PEGxx) _b is a polyethylene glycol derivative selected from the group consisting of (TTDS) ₂ , (TTDS) ₃ , (PEG ₂ DGA) ₃ , (PEG ₂ ) ₃ , (PEG ₂ ) ₄ and (PEG ₂ ) ₅ .

As stated previously, gE, which can also be represented as γE, gGlu or γGlu, is gamma-glutamic acid. This amino acid is characterized by the following structure:

where is the sign , when represented in formula (II) as (gE) _c , represents a covalent bond to _Cd , and represents a covalent bond with the (PEGxx) _b group.

_Cd represents a linear saturated C ₁₂ -C ₂₂ acyl group, in particular a linear saturated acyl group selected from the group consisting of the acyl groups C ₁₂ (Lau), C ₁₄ (Myr), C ₁₅ (Penta), C ₁₆ ( Palm), C ₁₇ (Hepta), C ₁₈ (Stea), C ₂₀ (Eico) and C ₂₂ (Doco). In one embodiment, C _k is a linear saturated acyl group selected from the group consisting of C ₁₂ (Lau), C ₁₄ (Myr), C ₁₅ (Penta), C ₁₆ (Palm), C ₁₇ (Hepta) acyl groups or C ₁₈ (Stea), in particular a linear saturated C ₁₄ -, C ₁₆ - or C ₁₈ acyl group and even more particularly a linear C ₁₆ - or C ₁₈ acyl group.

In a specific embodiment C_d represents a linear saturated C₁₂acyl group. Linear saturated C₁₂the acyl group of the present invention is a lauroyl group (also represented as "Lau" in this text).

In a specific embodiment C_d is a linear saturated C₁₄acyl group. Linear saturated C₁₄the acyl group of the present invention is a myristoyl group (also represented as "Myr" herein).

In a specific embodiment C_d is a linear saturated C₁₅acyl group. Linear saturated C₁₅the acyl group of the present invention is a pentadecanoyl group (also represented as "Penta" in this text).

In a specific embodiment C_d is a linear saturated C₁₆acyl group. Linear saturated C₁₆the acyl group of the present invention is a palmitoyl group (also represented as "Palm" in this text).

In a specific embodiment C_d represents a linear saturated C₁₇acyl group. Linear saturated acyl group C₁₇ of the present invention is a heptadecanoyl group (also represented as "Hepta" in this text).

In another specific embodiment, C_d is a linear saturated C₁₈acyl group. Linear saturated C₁₈the acyl group of the present invention is a stearoyl group (also represented as "Stea" in this text).

In another specific embodiment, C_d is a linear saturated C₂₀acyl group. Linear saturated C₂₀the acyl group of the present invention is an eicosanol group (also represented as "Eico" in this text).

In another specific embodiment, C_d is a linear saturated C₂₂acyl group. Linear saturated C₂₂the acyl group of the present invention is a docosanol group (also represented as "Doco" in this text).

In a specific embodiment, Z is selected from the group consisting of

-(TTDS) ₂ -(gamma-glutamic acid) ₃ -palmitoyl (-(TTDS) ₂ -(gE) ₃ -Palm), -(TTDS) ₃ -(gamma-glutamic acid) ₃ -palmitoyl (-(TTDS) ₃ -(gE) ₃ -Palm), -(PEG ₂ DGA) ₃ -(gamma-glutamic acid) ₃ -palmitoyl (-(PEG ₂ DGA) ₃ -(gE) ₃ -Palm), -(PEG ₂ ) ₄ -(gamma-glutamic acid) ₃ -palmitoyl

(-(PEG ₂ ) ₄ -(gE) ₃ -Palm), -(TTDS) ₂ -(gamma-glutamic acid) ₂ -palmitoyl (-(TTDS) ₂ -(gE) ₂ -Palm), -(TTDS) ₂ -(gamma-glutamic acid) ₃ -stearoyl (-(TTDS) ₂ -(gE) ₃ -Stea), -(TTDS) ₃ -(gamma-glutamic acid) ₃ -stearoyl (-(TTDS) ₃ -(gE ) ₃ -Stea), -(PEG ₂ DGA) ₃ -(gamma-glutamic acid) ₃ -stearoyl (-(PEG ₂ DGA) ₃ -(gE) ₃ -Stea), -(PEG ₂ DGA) ₃ -(gamma -glutamic acid) ₄ -stearoyl (-(PEG ₂ DGA) ₃ -(gE) ₄ -Stea), -(PEG ₂ ) ₃ -(gamma-glutamic acid) ₃ -palmitoyl

(-(PEG ₂ ) ₃ -(gE) ₃ -Palm), -(PEG ₂ ) ₄ -(gamma-glutamic acid) ₃ -stearoyl (-(PEG ₂ ) ₄ -(gE) ₃ -Stea),

-(PEG ₂ ) ₅ -(gamma-glutamic acid) ₃ -palmitoyl (-(PEG ₂ ) ₅ -(gE) ₃ -Palm), -(PEG ₂ ) ₅ -(gamma-glutamic acid) ₄ -palmitoyl (- (PEG ₂ ) ₅ -(gE) ₄ -Palm), -(TTDS) ₃ -(gamma-glutamic acid) ₄ -stearoyl (-(TTDS) ₃ -(gE) ₄ -Stea), -(TTDS) ₂ - (gamma-glutamic acid) ₄ -palmitoyl (-(TTDS) ₂ -(gE) ₄ -Palm), -(TTDS) ₃ -(gamma-glutamic acid) ₂ -stearoyl (-(TTDS) ₃ -(gE) ₂ -Stea) and

-(TTDS) ₂ -(gamma-glutamic acid) ₄ -stearoyl (-(TTDS) ₂ -(gE) ₄ -Stea), in a more specific embodiment, Z is selected from the group consisting of -(TTDS) ₂ -(gE ) ₃ -Palm,

-(TTDS) ₃ -(gE) ₃ -Palm, -(PEG ₂ DGA) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE) ₃ -Palm, -(TTDS) ₂ -(gE ) ₂ -Palm, -(TTDS) ₂ -(gE) ₃ -Stea, -(TTDS) ₃ -(gE) ₃ -Stea, -(PEG ₂ ) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE) ₃ -Stea and -(TTDS) ₂ -(gE) ₄ -Palm, in a special embodiment Z is selected from the group consisting of -(TTDS) ₃ -(gE) ₃ -Palm, -(TTDS) ₂ -(gE) ₃ -Stea and -(TTDS) ₃ -(gE) ₃ -Stea, for example -(TTDS) ₃ -(gE) ₃ -Palm and -(TTDS) ₃ -(gE) ₃ -Stea.

In all of these Z groups, the first symbol "-" represents the covalent bond between the Z group and the side chain nitrogen atom of the X ₂₅ lysine structure.

Accordingly, if the group Z is represented, for example, in the form

-(TTDS) ₂ -(gamma-glutamic acid) ₃ -palmitoyl (also represented as -(TTDS) ₂ -(gE) ₃ -Palm), the first TTDS group is bonded to the side chain nitrogen of structure X ₂₅ . A covalent bond also links the second TTDS group, while another covalent bond links this second TTDS group to the first gamma-glutamic acid (gE). This first gamma-glutamic acid (gE) is itself linked through a covalent bond to a second gamma-glutamic acid (gE), this second gamma-glutamic acid (gE) is linked through another covalent bond to a third gamma-glutamic acid (gE), and this the third group in the form of gamma-glutamic acid (gE) is additionally linked through a covalent bond to the palmitoyl group (Palm).

It will further be understood from the present application that the group Z of the present invention, represented for example as -(TTDS) ₂ -(gamma-glutamic acid) ₃ -palmitoyl (also represented as -(TTDS) ₂ -(gE) ₃ -Palm), could also be represented as

-TTDS-TTDS-gE-gE-gE-Palm.

The same applies subject to necessary modifications for other represented Z groups according to the present invention.

According to a specific embodiment, the peptide of the present invention is characterized by formula (Ia):

N _ter -Ac-LEGREX ₁₅ -VRX ₁₈ -X ₁₉ -I-Aib-Aib-EGX ₂₅ -STX ₂₈ -X ₂₉ -X ₃₀ -RX ₃₂ -X ₃₃ -NH ₂ -C _ter ,

Where

N _ter represents the N-terminal region of the peptide;

C _ter represents the C-terminal region of the peptide;

Ac represents an acetyl group;

L represents leucine;

E represents glutamic acid;

G represents glycine;

R represents arginine;

X ₁₅ is an amino acid selected from the group consisting of lysine, arginine, homolysine, glutamine, phenylalanine and leucine;

V represents valine;

X ₁₈ is an amino acid selected from the group consisting of alanine and 2-aminoisobutyric acid;

X ₁₉ is an amino acid selected from the group consisting of lysine,

Nε-acetyllysine, glutamine and citrulline;

I is isoleucine;

Aib is 2-aminoisobutyric acid;

X ₂₅ has the following structure:

wherein

- * represents a covalent bond with the glycine preceding X ₂₅ in formula (Ia);

- represents a covalent bond with the serine following X ₂₅ in formula (Ia); And

Z is selected from the group consisting of

-(TTDS) ₂ -(gE) ₃ -Palm, -(TTDS) ₃ -(gE) ₃ -Palm, -(PEG ₂ DGA) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE ) ₃ -Palm, -(TTDS) ₂ -(gE) ₂ -Palm, -(TTDS) ₂ -(gE) ₃ -Stea, -(TTDS) ₃ -(gE) ₃ -Stea,

-(PEG ₂ DGA) ₃ -(gE) ₃ -Stea, -(PEG ₂ DGA) ₃ -(gE) ₄ -Stea, -(PEG ₂ ) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE) ₃ -Stea, -(PEG ₂ ) ₅ -(gE) ₃ -Palm, -(PEG ₂ ) ₅ -(gE) ₄ -Palm, -(TTDS) ₃ -(gE) ₄ -Stea,

-(TTDS) ₂ -(gE) ₄ -Palm, -(TTDS) ₃ -(gE) ₂ -Stea and -(TTDS) ₂ -(gE) ₄ -Stea, where

gE is gamma-glutamic acid;

Palm is palmitoyl, and

Stea is stearoyl;

S represents serine;

T represents threonine;

X ₂₈ is an amino acid selected from the group consisting of tryptophan and phenylalanine;

X ₂₉ is an amino acid selected from the group consisting of serine, D-serine and

2-aminoisobutyric acid;

X ₃₀ is an amino acid selected from the group consisting of 2-aminoisobutyric acid, α-methyllysine, D-lysine and lysine;

X ₃₂ is an amino acid selected from the group consisting of lysine, alanine and arginine; And

X ₃₃ is an amino acid selected from lysine and Nε-acetyllysine;

or a salt or solvate thereof.

In accordance with a specific embodiment, the peptide of the present invention has an amino acid sequence selected from the group consisting of the amino acid sequences identified by SEQ ID NO: 1-97. In particular, the peptide of the present invention has an amino acid sequence selected from the group consisting of the amino acid sequences under reference SEQ ID NO: 1-32, 34-37, 39, 42, 44, 45, 47-49, 51 and 54-97 .

In a specific embodiment, for a peptide characterized by the following formula (Ia), as described above,

X ₁₉ is an amino acid selected from the group consisting of

Nε-acetyllysine and citrulline;

X ₂₅ has the following structure:

wherein

-* represents a covalent bond with the glycine preceding X ₂₅ in formula (Ia);

- represents a covalent bond with the serine following X ₂₅ in formula (Ia); And

Z is selected from the group consisting of

-(TTDS) ₂ -(gE) ₃ -Palm, -(TTDS) ₃ -(gE) ₃ -Palm, -(PEG ₂ DGA) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE ) ₃ -Palm, -(TTDS) ₂ -(gE) ₂ -Palm, -(TTDS) ₂ -(gE) ₃ -Stea, -(TTDS) ₃ -(gE) ₃ -Stea,

-(PEG ₂ ) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE) ₃ -Stea and -(TTDS) ₂ -(gE) ₄ -Palm, where

gE is gamma-glutamic acid;

Palm is palmitoyl, and

Stea is stearoyl;

X ₃₂ is an amino acid selected from the group consisting of lysine and alanine; And

X ₃₃ is Nε-acetyllysine

or a salt or solvate thereof.

In accordance with another embodiment, the peptide of the present invention has an amino acid sequence selected from the group consisting of the amino acid sequences identified by SEQ ID NO: 1-30.

In a specific embodiment, the peptide of the present invention characterized by formula (Ia) is such that

N _ter represents the N-terminal region of the peptide;

C _ter represents the C-terminal region of the peptide;

Ac represents an acetyl group;

L represents leucine;

E represents glutamic acid;

G represents glycine;

R represents arginine;

X ₁₅ is an amino acid selected from the group consisting of lysine and homolysine;

V represents valine;

X ₁₈ represents alanine;

X ₁₉ is an amino acid selected from the group consisting of

Nε-acetyllysine and citrulline;

I is isoleucine;

Aib is 2-aminoisobutyric acid;

X ₂₅ has the following structure:

wherein

-* represents a covalent bond with the glycine preceding X ₂₅ in formula (Ia);

- represents a covalent bond with the serine following X ₂₅ in formula (Ia); And

Z is selected from the group consisting of -(TTDS) ₂ -(gE) ₂ -Palm, -(TTDS) ₂ -(gE) ₃ -Palm,

-(TTDS) ₂ -(gE) ₄ -Palm, -(TTDS) ₃ -(gE) ₃ -Palm, -(PEG ₂ DGA) ₃ -(gE) ₃ -Palm, -(TTDS) ₂ -(gE) ₃ -Stea, -(TTDS) ₃ -(gE) ₃ -Stea and -(PEG ₂ ) ₄ -(gE) ₃ -Stea, where

gE is gamma-glutamic acid;

Palm is palmitoyl, and

Stea is stearoyl;

S represents serine;

T represents threonine;

X ₂₈ is an amino acid selected from the group consisting of tryptophan and phenylalanine;

X ₂₉ represents serine;

X ₃₀ is an amino acid selected from the group consisting of 2-aminoisobutyric acid and α-methyllysine;

X ₃₂ is an amino acid selected from the group consisting of lysine, alanine and arginine; And

X ₃₃ is an amino acid selected from lysine and Nε-acetyllysine;

or a salt or solvate thereof.

In a special embodiment, the peptide of the present invention characterized by formula (Ia) is such that

N _ter represents the N-terminal region of the peptide;

C _ter represents the C-terminal region of the peptide;

Ac represents an acetyl group;

L represents leucine;

E represents glutamic acid;

G represents glycine;

R represents arginine;

X ₁₅ represents lysine;

V represents valine;

X ₁₈ represents alanine;

X ₁₉ is Nε-acetyl-lysine;

I is isoleucine;

Aib is 2-aminoisobutyric acid;

X ₂₅ has the following structure:

wherein

-* represents a covalent bond with the glycine preceding X ₂₅ in formula (Ia);

- represents a covalent bond with the serine following X ₂₅ in formula (Ia); And

Z is selected from the group consisting of -(TTDS) ₃ -(gE) ₃ -Palm, -(TTDS) ₂ -(gE) ₃ -Stea,

-(TTDS) ₃ -(gE) ₃ -Stea and -(PEG ₂ ) ₄ -(gE) ₃ -Stea, where

gE is gamma-glutamic acid;

Palm is palmitoyl, and

Stea is stearoyl;

S represents serine;

T represents threonine;

X ₂₈ is an amino acid selected from the group consisting of tryptophan and phenylalanine;

X ₂₉ represents serine;

X ₃₀ is an amino acid selected from the group consisting of 2-aminoisobutyric acid and α-methyllysine;

X ₃₂ is an amino acid selected from the group consisting of lysine, alanine and arginine; And

X ₃₃ is an amino acid selected from lysine and Nε-acetyllysine;

or a salt or solvate thereof.

According to a specific embodiment, the peptide of the present invention is characterized by formula (Ib):

N _ter -Ac-X ₁₀ -EGREX ₁₅ -VRX ₁₈ -X ₁₉ -IX ₂₁ -X ₂₂ -EGX 25 -SX ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -RX ₃₂ -X _{33 -NH 2} -C _ter ,

Where

N _ter represents the N-terminal region of the peptide;

C _ter represents the C-terminal region of the peptide;

Ac represents an acetyl group;

X ₁₀ is an amino acid selected from the group consisting of leucine, Nε-acetyllysine and 2-aminoisobutyric acid;

E represents glutamic acid;

G represents glycine;

R represents arginine;

X ₁₅ is an amino acid selected from the group consisting of lysine, arginine, homolysine, glutamine, phenylalanine and leucine;

V represents valine;

X ₁₈ is an amino acid selected from the group consisting of alanine, 2-aminoisobutyric acid and Nε-acetyllysine;

X ₁₉ is an amino acid selected from the group consisting of lysine,

Nε-acetyllysine, glutamine and citrulline;

I is isoleucine;

X ₂₁ is an amino acid selected from the group consisting of 2-aminoisobutyric acid and alanine;

X ₂₂ is an amino acid selected from the group consisting of 2-aminoisobutyric acid and isoleucine;

X ₂₅ has the following structure:

wherein

- * represents a covalent bond with the glycine preceding X ₂₅ in formula (Ia);

- represents a covalent bond with the serine following X ₂₅ in formula (Ia); And

Z is selected from the group consisting of -(TTDS) ₂ -(gE) ₃ -Palm, -(TTDS) ₃ -(gE) ₃ -Palm, -(PEG ₂ DGA) ₃ -(gE) ₃ -Palm, -( PEG ₂ ) ₄ -(gE) ₃ -Palm, -(TTDS) ₂ -(gE) ₂ -Palm,

-(TTDS) ₂ -(gE) ₃ -Stea, -(TTDS) ₃ -(gE) ₃ -Stea, -(PEG ₂ DGA) ₃ -(gE) ₃ -Stea, -(PEG ₂ DGA) ₃ -( gE) ₄ -Stea, -(PEG ₂ ) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE) ₃ -Stea, -(PEG ₂ ) ₅ -(gE) ₃ -Palm, -( PEG ₂ ) ₅ -(gE) ₄ -Palm, -(TTDS) ₃ -(gE) ₄ -Stea, -(TTDS) ₂ -(gE) ₄ -Palm, -(TTDS) ₃ -(gE) ₂ -Stea ,

-(TTDS) ₂ -(gE) ₄ -Stea, -(TTDS) ₄ -(gE) ₃ -Stea, -(TTDS) ₃ -(gE) ₄ -Palm, -(TTDS) ₄ -(gE) ₃ - Palm, -(TTDS) ₃ -(gE) ₃ -Myr and -(TTDS) ₃ -(gE) ₄ -Myr, where

gE is gamma-glutamic acid;

Palm is palmitoyl, and

Stea is stearoyl;

S represents serine;

X ₂₇ is an amino acid selected from the group consisting of threonine, glutamine, arginine and lysine;

X ₂₈ is an amino acid selected from the group consisting of tryptophan, phenylalanine, 5-chlorotryptophan, α-methylphenylalanine, 4-fluorophenylalanine and 5-fluorotryptophan;

X ₂₉ is an amino acid selected from the group consisting of serine, D-serine,

2-aminoisobutyric acid, Nε-acetyllysine, threonine and valine;

X ₃₀ is an amino acid selected from the group consisting of 2-aminoisobutyric acid, α-methyllysine, D-lysine, lysine, homolysine and arginine;

X ₃₂ is an amino acid selected from the group consisting of lysine, alanine, arginine and Nε-acetyllysine; And

X ₃₃ is an amino acid selected from lysine, Nε-acetyllysine and arginine;

or a salt or solvate thereof.

In particular, Z may be selected from the group consisting of

-(TTDS) ₂ -(gE) ₃ -Palm, -(TTDS) ₃ -(gE) ₃ -Palm, -(PEG ₂ DGA) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE ) ₃ -Palm, -(TTDS) ₂ -(gE) ₂ -Palm, -(TTDS) ₂ -(gE) ₃ -Stea, -(TTDS) ₃ -(gE) ₃ -Stea, -(PEG ₂ DGA) ₃ -(gE) ₃ -Stea, -(PEG ₂ ) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE) ₃ -Stea, -(PEG ₂ ) ₅ -(gE) ₃ -Palm , -(TTDS) ₃ -(gE) ₄ -Stea, -(TTDS) ₂ -(gE) ₄ -Palm, -(TTDS) ₂ -(gE) ₄ -Stea, -(TTDS) ₄ -(gE) ₃ -Stea, -(TTDS) ₃ -(gE) ₄ -Palm, -(TTDS) ₄ -(gE) ₃ -Palm, -(TTDS) ₃ -(gE) ₃ -Myr and -(TTDS) ₃ -(gE ) ₄ -Myr.

In a specific embodiment of the present invention, the peptide of the present invention has an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 6, 7, 9, 10, 11, 12, 13, 20, 21, 22, 26, 28 and thirty.

In a specific embodiment of the present invention, the peptide of the present invention has an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 6, 7, 9-12, 20-22, 26, 28, 30-34, 45, 47- 49, 51, 54-62, 64, 67-69, 71-93, 96 and 97. As stated above herein and illustrated in the accompanying examples, these peptides are particularly advantageous since they all have an EC ₅₀ of 1 nM or less.

Specifically, the peptide of the present invention has an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 6, 7, 13, 20, 26 and 30.

Specifically, the peptide of the present invention has an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 6, 7, 20, 26, 30-34, 45, 48, 49, 51, 54-61, 67, 71 73, 75-79, 81, 83-92 and 97. As illustrated in the accompanying examples, the peptides according to this embodiment are particularly advantageous since they all have an EC ₅₀ of 0.5 nM or less.

In a specific embodiment, the peptide of the present invention has an amino acid sequence selected from the group consisting of the amino acid sequences referenced SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 20, and in particular has amino acid sequence under reference SEQ ID NO: 3.

The peptide of the present invention can be prepared using any technique known per se prior art, such as, without limitation, any chemical, biological, genetic or enzymatic technique, either alone or in combination. Knowing the amino acid sequence of the desired sequence, one skilled in the art can readily prepare said polypeptides using standard polypeptide production techniques, even if unnatural amino acids are used in accordance with the methods described herein.

For example, the peptides of the present invention can be synthesized using a well-known solid phase method, particularly using a commercially available peptide synthesis apparatus (such as those manufactured by Applied Biosystems, Foster City, Calif., Gyros Protein technologies, Tucson, Arizona, or CEM corporation , Matthews, NC) and following the manufacturer's instructions.

Examples of suitable methods are illustrated in the accompanying examples.

The peptide of the present invention may be labeled with at least one of a detectable molecule or substance, particularly selected from the group consisting of enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials and radioactive materials.

However, it is important that the label does not alter or interfere with the biological activity of the peptide of interest as previously defined, i.e., does not prevent or alter the ability of the peptide to bind to and activate the RXFP1 receptor.

Preferred detectable molecules or substances for a nanomaterial support are those that can be detected externally in a non-invasive manner after administration in vivo .

The molecules or substances to be detected are well known to one skilled in the art.

Such a labeled peptide of the present invention can be used in a diagnostic and/or imaging method.

In addition, the present inventors have observed that the half-life, and in particular the in vivo half-life, of the peptides of the present invention is significantly higher than that of relaxin.

Indeed, relaxin is rapidly eliminated by the kidneys and cannot be used in chronic conditions. The recombinant hormone has a very short half-life in vivo (as illustrated in monkey and man in BL Ferraiolo et al. Pharm. Res. (1991), 8, 1032 and in SA Chen et al. Pharm. Res. (1993), 10, 834) and requires intravenous delivery. The half-life of relaxin is indeed so short that continuous infusion over several hours in a hospital setting may be required to administer it to an individual in need thereof, particularly to an individual suffering from an acute disease or disorder such as, for example, congestive heart failure. Replacing relaxin in this treatment with relaxin peptides having an improved in vivo half-life advantageously allows this restrictive treatment to be replaced by a simpler one, such as once daily administration, for example by the intravenous or subcutaneous route.

Accordingly, the relaxin peptides of the present invention that have the ability of relaxin to activate RXFP1, and in particular peptides that are long-acting RXFP1 agonists, have the potential for broader therapeutic use, including acute or chronic heart failure.

Compositions and drugs

The present application also relates to a drug or pharmaceutical composition containing at least one peptide of the present invention, as described above, or one of its pharmaceutically acceptable salts or solvates and at least one pharmaceutically acceptable carrier.

At least one peptide of the present invention is present in the drug or pharmaceutical composition of the present invention as an active substance.

The composition or drug of the present invention is in a form suitable for administration to mammals.

The composition or drug of the present invention can be administered, for example, orally, parenterally, intravenously, rectally, transdermally, topically or by inhalation. In particular, the composition of the present invention is administered intravenously or subcutaneously.

According to a particular embodiment, the pharmaceutically acceptable carrier of the composition of the present invention is suitably selected from the group consisting of an injection carrier liquid such as sterile water for injection; and an aqueous solution such as saline.

The composition or medicinal product of the present invention may contain the peptides of the present invention in the range from 0.01 mg/ml to 30 mg/ml, in particular from 0.3 mg/ml to 3 mg/ml.

The drug or pharmaceutical composition of the present invention may contain at least one peptide of the present invention as the sole active substance or may also contain at least one other active substance, if said other active substance does not interfere with the biological activity of the peptide in accordance with the present invention .

The pharmaceutical composition or medicinal product in accordance with the present invention may further contain at least one antioxidant, dispersant, emulsifier, antifoam, flavoring, preservative, solubilizer and/or coloring agent, provided that this/these additional substances do not interfere with the biological properties of the peptides according to the present invention.

The sterile compositions of the present invention for parenteral administration may, in particular, be aqueous or non-aqueous solutions, suspensions or emulsions. Solvents or carrier media that may be used include water, propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, injectable organic esters, eg ethyl oleate, or other suitable organic solvents. These compositions may also contain auxiliary agents, in particular wetting agents, tonicity agents, emulsifiers, dispersants and stabilizers. Sterilization can be accomplished in several ways, for example, by aseptic filtration, by incorporating sterilants into the composition, by irradiation, or by heat. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injection medium.

Compositions for topical use may be, for example, nasal drops or aerosols.

For subcutaneous, intramuscular or intravenous administration, the peptides used according to the present invention are converted, if desired, by means of substances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries, into a solution, suspension or emulsion. Examples of suitable solvents are water, physiological saline or alcohols such as ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

In a specific embodiment, a composition of the present invention, a drug of the present invention, or a peptide of the present invention, or one of its pharmaceutically acceptable salts or solvates, is administered to an individual by the parenteral route and, in particular, is administered transdermally, intravenously, subcutaneously or intramuscularly, in particular intravenously or subcutaneously

Methods for preparing parenterally administered compositions will be apparent to those skilled in the art and, for example, are described in more detail in Remington's Pharmaceutical Science, 15 ^th ed., Mack Publishing Company, Easton, Pennsylvania.

Administration of a composition of the present invention or a peptide of the present invention to an individual may be systemic administration or administration limited to a tissue, organ and/or site of a single body where the presence of, for example, fibrosis is known, suspected or to be determined.

Application of peptides and compositions

The present invention relates to a peptide of the present invention, a pharmaceutically acceptable salt or solvate thereof of the present invention for use as a drug.

Moreover, the present invention also relates to a pharmaceutical composition according to the present invention for use as a medicine.

Furthermore, the present invention relates to a peptide of the present invention, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present invention for use in the treatment and/or prevention of various diseases or conditions associated with the RXFP1 receptor, more particularly diseases or conditions selected from

- group consisting of fibrosis; fibrotic diseases, in particular systemic sclerosis, scleroderma and fibromyalgia; idiopathic pulmonary fibrosis; kidney diseases associated with fibrosis; pulmonary hypertension and preeclampsia;

- the group consisting of diseases of the heart and blood vessels, in particular the group consisting of acute or chronic heart failure, systolic or diastolic heart failure, coronary heart disease, atherosclerosis, microvascular angina and cardiovascular complications of diabetes; and/or

- a group consisting of types of renal failure, in particular renal dysfunction in cirrhosis; chronic renal failure and acute renal failure.

In one aspect, such a peptide, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the present invention is administered once daily, particularly by the intravenous or subcutaneous route.

The dose of the peptide or its pharmaceutically acceptable salt or solvate to be administered and the frequency of administration depend on the desired effect, activity and duration of action of the compounds used; additionally also on the nature and severity of the disease or condition being treated, and on the sex, age, weight and individual susceptibility of the mammal being treated. Typically, the physician will determine the appropriate dosage based on age and weight, as well as all other factors specific to the individual being treated.

Also described is a method of preventing and/or treating in an individual a disease or condition associated with the relaxin receptor RXFP1, comprising administering to said individual at least one peptide of the present invention, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present invention containing at least one peptide of the present invention, or a therapeutically effective amount of at least one peptide of the present invention, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present invention containing at least one peptide of the present invention.

As previously stated, said disease or condition is specifically selected from

- group consisting of fibrosis; fibrotic diseases, in particular systemic sclerosis, scleroderma and fibromyalgia; idiopathic pulmonary fibrosis; kidney diseases associated with fibrosis; pulmonary hypertension and preeclampsia; - the group consisting of diseases of the heart and blood vessels, in particular the group consisting of acute or chronic heart failure, systolic or diastolic heart failure, coronary heart disease, atherosclerosis, microvascular angina and cardiovascular complications of diabetes; and/or

- a group consisting of types of renal failure, in particular renal dysfunction in cirrhosis; chronic renal failure and acute renal failure.

The following describes the use of at least one peptide of the present invention, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present invention containing at least one peptide of the present invention, or a therapeutically effective amount of at least one peptide of the present invention, pharmaceutically an acceptable salt or solvate or pharmaceutical composition of the present invention containing at least one peptide of the present invention for the manufacture of a medicament for the prevention and/or treatment in an individual of a disease or condition associated with the relaxin receptor RXFP1.

The following describes the use of at least one peptide of the present invention, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present invention for the treatment and/or prevention of a disease or condition selected from

- group consisting of fibrosis; fibrotic diseases, in particular systemic sclerosis, scleroderma and fibromyalgia; idiopathic pulmonary fibrosis; kidney diseases associated with fibrosis; pulmonary hypertension and preeclampsia;

- the group consisting of diseases of the heart and blood vessels, in particular the group consisting of acute or chronic heart failure, systolic or diastolic heart failure, coronary heart disease, atherosclerosis, microvascular angina and cardiovascular complications of diabetes; and/or

- a group consisting of types of renal failure, in particular renal dysfunction in cirrhosis; chronic renal failure and acute renal failure.

The present invention is illustrated by the following examples, provided for illustrative purposes only.

Examples

Example 1. Synthesis of peptides according to the present invention

Materials used

Various Rink amide resins were used to synthesize the C-terminal amide peptides of the present invention:

- 4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)phenoxy resin, sold by Chem-Impex; or

- 4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)phenoxyacetamidomethyl resin available from Millipore Merck;

They were loaded in the range of 0.2 to 0.4 mmol.g.

Fmoc (fluorenylmethyloxycarbonyl) protected natural amino acids were purchased from various sources, i.e., Protein Technologies Inc., Merck Biosciences, Novabiochem, Iris Biotech, Bachem, Chem-Impex International or MATRIX Innovation.

The following standard amino acids were used during the synthesis: Fmoc-L-Ala-OH, Fmoc-L-Arg(Pbf)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Glu(OtBu)-OH, Fmoc -L-Glu-OtBu, Fmoc-Gly-OH, Fmoc-L-Ile-OH, Fmoc-L-Leu-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L-Met-OH, Fmoc- L-Phe-OH, Fmoc-L-Ser(tBu)-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L-Trp(Boc)-OH, Fmoc-L-Tyr(tBu)-OH and Fmoc-L-Val-OH.

In addition, the following specific amino acids were purchased from the same suppliers listed above: Fmoc-L-hArg(Pbf)-OH, Fmoc-L-Cit-OH, Fmoc-L-Arg(Me, Pbf)-OH, Fmoc- L-hLys(Boc)-OH, Fmoc-L-Orn(Boc)-OH, Fmoc-L-Lys(Dde)-OH, Fmoc-L-Lys(ivDde)-OH, Fmoc-L-Lys(Mtt) -OH, Fmoc-L-Lys(aloc)-OH, Fmoc-L-Lys(Ac)-OH, Fmoc-Aib-OH, Fmoc-L-α-Me-Ser(tBu)-OH, Fmoc-L- α-Me-Lys(Boc)-OH, Fmoc-L-α-Me-Arg(Pbf)-OH, Fmoc-L-α-Me-Leu-OH, Fmoc-L-Nle-OH and Fmoc-L- 1-Nal-OH, Fmoc-L-2-Nal-OH Fmoc-5-Wox-OH, Fmoc-Pfp-OH, Fmoc-L-α-Me-Trp-OH, Fmoc-L-α-Me-Phe -OH.

Ac Acetyl Aloc Allyloxycarbonyl Boc tert-Butyloxycarbonyl tBu tert-Butyl cAMP Cyclic adenosine monophosphate Dde 1-(4,4-Dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl ivDde 1-(4,4-Dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl DCM Dichloromethane DIC N, N'-Diisopropylcarbodiimide DIEA, DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DODT 2,2′-(Ethylenedioxy)diethanethiol EDT 1,2-Ethanedithiol Fmoc Fluorenylmethyloxycarbonyl T.F.A. Trifluoroacetic acid TIS, TIPS Triisopropylsilane HATU (2-(7-Aza-1H-benzotriazol-1-yl)-N, N,N',N'-tetramethylaminium hexafluorophosphate) HCTU O-(1H-6-Chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HPLC High performance liquid chromatography HTRF HTRF homogeneous time-separated fluorescence LC/MS Liquid chromatography/mass spectrometry Laur Lauroil mmt Monomethoxytrityl Mtt 4-Methyltrityl Myr Miristoil NMP 1-Methylpyrrolidin-2-one Oxyma Ethyl 2-cyano-2-(hydroxyamino)acetate (Oxyma pureTM) Pbf 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl RP-HPLC Reverse phase high performance liquid chromatography RT Retention time T.F.A. Trifluoroacetic acid Trt Trityl, triphenylmethyl UV Ultraviolet UPLC Ultra-performance liquid chromatography

To synthesize the C-terminal lipidated peptides of the present invention, orthogonally protected lysine was used as described later herein.

1. A. General method used to synthesize the peptides of the present invention

The peptides of the present invention with the sequence SEQ ID NO: 1-97 were synthesized based on the method presented in Figures 1 and 2.

0.2 mmol of Rink AM amide resin was placed in a CEM Liberty blue microwave peptide synthesis apparatus to assemble the complete peptide sequence. (see figure 1).

The entire synthesis was carried out in DMF as solvent. The peptide was synthesized using a standard heating protocol for a scale of 0.1 to 0.2 mmol.

Standard heating protocol: irradiation at 170 watts, 75°C, 15 seconds, then irradiation at 30 watts, 90°C, 120 sec.

Removal of the protecting group was carried out using 20% v/v. piperidine in DMF followed by 3 washing steps with DMF.

Heating protocol for deprotection: irradiation at 170 watts, 75°C, 15 seconds, then irradiation at 30 watts, 90°C, 50 seconds.

Amino acid coupling was performed using 5 equiv. Fmoc-AA as 0.2 M solutions in DMF using 5 eq. 0.5 M N,N'-diisopropylcarbodiimide (DIC) and 5 eq. 1 M Oxyma (ethyl 2-cyano-2-(hydroxyamino)acetate (oxyma pure™)) as reagents for coupling reactions.

For best final yield, each amino acid required double coupling at 90°C for 120 seconds. For 2-aminoisobutyric acid at positions X ₂₁ and X ₂₂ and serine at position X ₂₉ according to formula (I), according to the present invention, a ternary coupling was used at 90°C for 2 minutes.

In the case of expensive amino acid derivatives, such as Fmoc-α-methyllysine(Boc)-OH, it may be advantageous to perform manual coupling using 3 eq. amino acids and 3 eq. coupling agents such as HATU or HCTU at room temperature for 1-18 hours or using DIC and Oxyma Pure™ with microwave heating for 120 seconds.

At position X ₂₅ , a derivative of Fmoc-lysine-OH was used, bearing an orthogonal protecting group on the nitrogen atom of the side chain. Selective removal of the protecting group allowed modification of this amino acid side chain.

At the end of the synthesis, deprotection of Fmoc was performed manually using 20% v/v. piperidine in DMF twice for 30 minutes at room temperature.

Acetylation was carried out at the N-terminus by treatment with 5-10 equiv. acetic anhydride and 5-10 eq. DIEA in DMF for 15 min. The resin containing the fully protected peptide was then washed with DCM/DMF/DCM 3 times each and dried under vacuum.

The Nε lysine protecting group at position X ₂₅ (Dde, ivDde, Aloc or Mtt) was then removed using dilute hydrazine in DMF (Dde, ivDde), phenylsilane or dimethylaminoborane in the presence of a palladium(0) catalyst in DCM (aloc) or 1% TFA in DCM (Mtt).

Z groups were then attached to the side chain nitrogen of lysine X ₂₅ on a solid support according to the following steps.

When the lysine at position X ₂₅ was protected on its side chain by Dde or

iv-Dde, peptide resin was transferred into a 50 ml polypropylene syringe. 80 ml of a solution of 5% hydrazine in DMF was percolated through the resin followed by rinsing with DMF (3 times). The reaction was monitored using the Kaiser test.

When the lysine at position _X25 was protected on its side chain by an allyloxycarbonyl group (aloc), the peptide resin was transferred to a 50 ml polypropylene syringe and allowed to swell in dichloromethane and treated with 20 eq. phenylsilane (PhSiH3) (or borane-dimethylamine complex ((CH ₃ ) ₂ NH.BH ₃ ) and piperidine) and 10% (mol/mol) tetrakis-(triphenylphosphine) palladium (Pd(PPh ₃ ) ₄ ) for 2 hours in an argon atmosphere. This treatment was repeated until the original aloc-protected peptide was no longer detectable by UPLC/MS analysis after digestion of an aliquot of the resin.

When the reaction was complete, the resin was washed with dichloromethane, 1% DIEA in DMF, 5% diethyldithiocarbamate in DMF, DMF, 10% DIEA in DMF, DMF and dichloromethane (3 times each).

When the lysine at position X ₂₅ was protected on its side chain by a methyltrityl group (Mtt), the peptide resin was transferred to a 50 ml polypropylene syringe and allowed to swell in dichloromethane and treated with 10 ml of DCM/TIS/TFA mixture (88/5/2 ). After shaking for 1 hour, the solvent was discarded, the resin was washed with DCM, shaken with 10 ml of a mixture of DCM/DIEA (90/10) and washed several times with DCM.

Group Z PEGxx group(s) were introduced, if applicable for a given peptide of the present invention, by single acylation with 3 eq. Fmoc-PEGxx-OH for 18 hours with 3 eq. DIC and 3 eq. HOAt, monitoring reactions using the ninhydrin test (Kaiser). The resin was then treated with 20% v/v. piperidine in DMF deprotected with Fmoc (2×30 min) and washed 3 times with DMF. The steps of coupling Fmoc-PEGxx-OH, removing Fmoc and washing were repeated x times (x=0-5).

Then Fmoc-Glu-OtBu ((4S)-5-tert-butoxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxopentanoic acid), if gE was present in the Z group of the peptide of the present invention, was introduced by performing a single combinations with 3 eq. amino acids for 18 hours with 3 eq. DIC and 3 eq. HOAt, monitoring reactions using the Kaiser test.

The resin was then treated with 20% v/v. piperidine in DMF deprotected with Fmoc (2×30 min) and washed 3 times with DMF. The Fmoc removal and Fmoc-Glu-OtBu coupling steps were repeated y times (y=1-5).

The side chain was then lipidated using 3 equiv. Ck of lauric acid ( _C12 ), myristic acid ( _C14 ), pentadecanoic acid (C15), palmitic acid ( _C16 ), heptadecanoic acid ( _C17 ), stearic acid ( _{C18 )} , eicosanoic acid ( _C20 ) or docosanoic acid ( _C22 ) using 3 eq. DIC and 3 eq. HOAt in NMP using the corresponding acyl chlorides and DIEA as the base in dichloromethane or using the corresponding N-succinimidyl esters and DIEA as the base in DMF.

The reaction was monitored using the Kaiser test and left overnight.

The resin containing the fully protected peptide was then washed with DCM/DMF/DCM 3 times each and dried under vacuum.

1.B. Peptide Resin Cleavage

Upon completion of solid phase synthesis, the peptide was cleaved from the solid support by treatment with digestion reagent B: TFA/phenol/H ₂ O/TIPS (87.5%/5%/5%/2.5%/25 ml) for 3 h. (TIPS is triisopropylsilane)

In some cases, it may be advantageous to add a dithiol such as 1,2-ethanedithiol or DODT (2,2′-(ethylenedioxy)diethanethiol) (eg K cleavage reagent). The TFA solution containing the peptide was filtered and concentrated under reduced pressure at T < 30°C.

The desired product was precipitated with ice-cold MTBE or diethyl ether and centrifuged at 3000 rpm. within 30 min. The centrifuged pellet was then washed with ice-cold diethyl ether and centrifuged. This process was repeated three times.

In some cases, it may be necessary to process the crude peptide to remove unwanted by-products such as TFA esters, CO ₂ addition product at the indole tryptophan nitrogen atom (carbamic acid), and 2-tert-butylsulfanylethyl addition product at methionine residues.

To remove the CO ₂ addition product at the indole tryptophan nitrogen atom, the crude peptide was dissolved in water containing 10-20% CH ₃ CN, 5 mg/ml, and lyophilized.

To remove the 2-tert-butylsulfanylethyl addition product at Met, the crude peptide was dissolved (2 mg/ml) in a solution of H ₂ O/CH ₃ CN (50:50 v/v) containing 0.1% formic acid.

The mixture was shaken gently at 37°C overnight.

To remove TFA esters, the crude peptide was dissolved (2 mg/ml) in a solution of H ₂ O/CH ₃ CN (50:50 v/v) containing 0.1% formic acid. The mixture was gently shaken at 37°C for 1-4 hours.

In both cases, the crude peptide solution thus obtained was partially concentrated under reduced pressure and at T<30° C. and lyophilized.

1.C. Purification stage

Following any of the above methods specified for the synthesis of the peptide of the present invention, the specified peptide was purified before use.

80 mg of peptide was dissolved in 1.5 ml DMSO and purified using reverse phase high pressure liquid chromatography (RP-HPLC). RP-HPLC has been described later in this document.

Used GX271 Liquid Handler, 333/334 pumps and 151 Gilson UV/VIS system.

Two different systems were used to purify these peptides.

System A

- Column Waters Delta-Pack C4 15 µm 300Å. 250×20 mm;

- solution A: 0.1% trifluoroacetic acid (TFA) in H ₂ O;

- solution B: 0.1% TFA in acetonitrile;

- gradient: 15% B for 5 minutes; from 15% B to 50% B in 20 minutes;

- flow rate: 80 ml/min.

System B

- Column Waters CSH C18 5 µm, 250×50 mm, or Waters Sunfire C18 10 µm, 250×50 mm;

- solution A=0.1% TFA in water;

- solution B=0.1% TFA in acetonitrile;

- gradient: from 1% B to 18% B in 5 minutes; from 18% B to 28% B in 10 minutes; 28% B for 15 minutes; from 28% B to 48% B in 10 minutes; then wash the column from 48% B to 90% B in 10 minutes;

- flow rate: 150 ml/min.

The peptide of interest was eluted over a time interval of 35-40 min.

The gradient was adjusted slightly according to the polarity of each peptide, which is characterized by its retention time in the UHPLC analytical system.

Fractions containing pure peptide were then partially concentrated under reduced pressure at T<35°C and lyophilized to constant weight.

For certain application routes (eg in vivo testing) it has been advantageous to replace the TFA salt with an acetate salt. Three corresponding methods were used and described in the next part 1.D.

1.D. Acetate exchange

(i) Acetate exchange with TOYOPEARL® DEAE 650 C (Tosoh Corporation)

Ion exchange was performed using TOYOPEARL® DEAE 650 Grade C resin (weak anion exchange resin).

120 ml of resin were washed successively with 15 volumes of 1 M NaOH,

5 volumes of _H2O , 5 volumes of 1.6 M acetic acid, 5 volumes of 0.16 M acetic acid and finally 5 volumes of _H2O .

41.8 mg of peptide was then dissolved in 4 mL of distilled water, loaded into the resin, and stirred gently for 2 h.

Finally, the peptide was collected by elution, washed with water and lyophilized.

Peptide recovery: 35 mg (as acetate salt according to F19 NMR (400 MHz) 1028 ns).

(ii) Acetate exchange with Sepharose HiTrap Q HP column (strong anion exchange column)

In the second method, ion exchange was carried out using HiTrap Q HP.

The column (5 mL bed volume) was connected to a peristaltic pump set at 48 (4.5 mL/min) and washed with 50 mL (10 column volumes) of _H2O , 100 mL (20 column volumes) before loading the peptide. ) 1 M sodium acetate solution, 150 ml

(30 column volumes) of H ₂ O and using 50 ml (10 column volumes) of 0.16 M acetic acid solution.

The pure peptide was dissolved in 0.16 M acetic acid at 2 mg/mL, loaded slowly onto the column, and eluted at 4.5 mL/min.

The collected solution was dried by sublimation.

The efficiency of ion exchange was confirmed using F19 NMR (400 MHz) 1028 ns.

(iii) Acetate exchange with BIO RAD AG1X4® anion exchange resin

A 125 mL reactor equipped with a sintered glass bottom was charged with 6.2 g of BIO RAD AG1X4® anion exchange resin, dry mesh size 100-200 (OH form).

The resin was shaken with 3 x 100 mL of 1.6 M aqueous acetic acid (10% v/v) and 3 x 50 mL of 0.16 M aqueous acetic acid (1% v/v) on a stir plate for 20 minutes. with each one.

The purified peptide as TFA salt (100 mg) was dissolved in 50 ml of distilled water, poured onto the exchange resin and shaken on a stir plate for 120 min.

The aqueous solution was poured into a 100 ml round bottom flask and the resin was washed with 2 x 15 ml of 0.16 M aqueous acetic acid (1% v/v).

The combined solutions containing the peptide as an acetate salt were lyophilized to constant weight. Yield = 80 mg of peptide in the form of acetate salt.

The efficiency of ion exchange was confirmed using F19 NMR (400 MHz, 1028 ns) and/or ion chromatography.

Example 2: Exemplary Synthesis of Specific Peptides of the Present Invention

2.A Loading Fmoc-Lys(Ac)-OH onto Rink amide resin

In a 100 ml reactor equipped with sintered glass at the bottom, 6 g of AM Novabiochem or ChemImpex Rink amide resin (low loading 0.47 mmol/g) was swollen in 40 ml of DMF. The solvent was decanted and 30 ml of a 20% piperidine solution in DMF was added. After shaking for 15 minutes. the solvent was drained. This was repeated twice to ensure complete removal of the Fmoc protecting group. The resin was washed with 5 x 30 ml DMF.

In a separate flask, a solution containing Fmoc-Lys(Ac)-OH (3.5 g, 8 mmol, 3 eq.) HOBT.H ₂ 0 (1.3 g, 8.5 mmol) in 30 ml DMF was prepared. Diisopropylcarbodiimide (DIC) (1 g, 8.5 mmol) was added to this solution and after 5 min. the resulting mixture was added to the resin. The suspension was shaken on a stir plate for 4 hours or until the reaction was complete, as determined by the Kaiser test (ninhydrin test) on an aliquot of the resin.

The solvent was then discarded and the resin was washed 3 times with 30 ml DMF. The resin loaded with Fmoc-Lys(Ac)-NH ₂ was used immediately for subsequent steps or kept moist at 4°C until required.

2.B. Synthesis of peptide having SEQ ID NO: 3

The following synthesis was carried out using 5 batches of the resin obtained in step 2.A., corresponding to 0.2 mmol Fmoc-Lys(Ac)-NH ₂ each. Syntheses were performed separately for each individual batch using a CEM Liberty Blue microwave peptide synthesis apparatus to assemble the second and third residues of the peptide sequence (starting from the C terminus).

Peptide synthesis was performed using 0.5 M DIC/1 M Oxyma in DMF.

All amino acids were double coupled using a standard heating protocol.

The resin was removed from the synthesizer and Fmoc-α-methyl-lysine(Boc)-OH (3 eq.) was combined manually using 3 eq. Oxyma™ and 3 eq. DIC using microwave heating (75°C for 15 seconds and 90°C for 110 seconds). Completion of the reaction was monitored using the Kaiser test. If the result was positive, 3 equiv was added. DIC followed by microwave heating as described above.

Once the coupling of Fmoc-α-methyl-lysine (Boc)-OH was completed, the remainder of the peptide sequence was assembled using a CEM Liberty Blue microwave peptide synthesis apparatus.

All amino acids were double-coupled at 90°C as above, with the exception of aminoisobutyric acid at position 21 and serine at position 29, which were triple-coupled at 90°C for 2 minutes. Fmoc-Lys(Dde)-OH was used at position 25.

At the end of 5 syntheses, 5 batches of resin were pooled and transferred into a 50 ml polypropylene syringe and the peptide was acetylated to

N-terminally with acetic anhydride (944 µl, 10 mmol) in DMF (30 ml) for 20 minutes, repeating the cycle twice.

The Dde protecting group on the side chain of lysine 25 was then removed by percolating 50 mL of a 5% w/v solution. hydrazine in DMF followed by washes with DMF (5×20 ml). The reaction was monitored using the Kaiser test and digestion of an aliquot of resin and UPLC/MS analysis.

Three TTDS spacer units were administered by single coupling by performing the following procedure three times: A solution of Fmoc-TTDS-OH (1.62 g, 3 mmol) in 30 mL DMF was added to the resin, followed by the addition of HOAt (5 mL, 0. 6 ml solution in DMF, 3 mmol) and DIC (1 ml, 6 mmol). The syringe was stirred on a stirring table for 18 hours. The reaction was monitored using the Kaiser test. The resin was washed with DMF (2×30 ml). Then 30 ml of 20% v/v was added to the resin. piperidine in DMF. The syringe was mixed on a mixing table for 20 minutes. This deprotection procedure was repeated a second time and the resin was washed with DMF (2 x 30 ml) and dichloromethane (3 x 30 ml).

Three gamma-glutamic acid spacers were introduced by performing a double coupling of each Fmoc-Glu-OtBu. Thus, the following procedure was applied three times.

A solution of (4S)-5-tert-butoxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxopentanoic acid (Fmoc-Glu-OtBu) (1.275 g, 3 mmol) in 30 ml DMF was added to the resin, after followed by the addition of HOAt (5 ml of a 0.6 ml solution in DMF, 3 mmol) and DIC (1 ml, 6 mmol). The syringe was mixed on a stirring table for 4 hours. The resin was washed with DMF (2x20 ml) and the combination was repeated a second time. The reaction was monitored using the Kaiser test. The resin was washed with DMF (2×30 ml). Then 30 ml of 20% v/v was added to the resin. piperidine in DMF. The syringe was mixed on a mixing table for 20 minutes. This deprotection procedure was repeated a second time and the resin was washed with DMF (3 x 30 ml) and dichloromethane (3 x 30 ml).

Finally, the peptide was acylated with palmitic acid (768 mg, 3 mmol), HOAt (5 ml of 0.6 M solution in DMF, 3 mmol) and DIC activation (1 ml, 6 mmol) in DMF (30 ml) for 2 .5 hours. The resin was washed with DMF (2×30 ml) and dichloromethane (3×30 ml) and dried in vacuum.

Cleavage of the peptide from the resin was carried out using a solution of phenol (6.25 g), water (6.25 ml) and TIPS (3 ml) in TFA (QSP 125 ml) for 2.5 hours at room temperature. The resin was filtered and washed with 2×30 ml TFA. The combined filtrates were transferred to a 250 ml round bottom flask and partially concentrated in vacuo at T<30° C. and the peptide was precipitated by adding 100 ml of ice-cold MTBE and centrifuged at 3600 rpm. within 30 minutes.

The centrifuged sediment was then washed with ice-cold diethyl ether and centrifuged. This process was repeated three times. 4.3 g of crude peptide was obtained. The crude peptide was dissolved (10 mg/ml) in a solution of H ₂ O/CH ₃ CN (50:50 v/v) containing 0.1% formic acid, and the mixture was gently shaken at 37°C for 1 h. , partially concentrated and lyophilized.

Purification was performed using purification system A in 10 injections of 350 mg each and fractions containing pure desired peptide were lyophilized. The trifluoroacetate salt peptide was obtained as a white solid.

m=428 mg (17.5%)

UPLC/MS:

RT: 4.98 min. (analytical condition A), 99% purity (UV)

Observed mass, mass/charge (ion type): 1454.5 (M+3H); 1091.1 (M+4H); 873.1 (M+5H).

2.C. Synthesis of peptide having SEQ ID NO: 7

2 batches of resin obtained in 2.A., corresponding to 0.2 mmol Fmoc-Lys(Ac)-NH2 each (0.4 mmol total) were processed in parallel, following the same procedure as in example 2.B. After coupling of third (4S)-5-tert-butoxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxopentanoic acid (Fmoc-Glu-OtBu), the combined 2.6 g batches of resin were transferred into a 50-volume polypropylene syringe ml.

Then 30 ml of 20% v/v was added to the resin. piperidine in DMF. The syringe was mixed on a mixing table for 20 minutes. This deprotection procedure was repeated a second time and the resin was washed with DMF (3 x 30 ml) and dichloromethane (3 x 30 ml).

The peptide was acylated by adding a solution of stearoyl chloride (362 mg, 1.2 mmol) and DIPEA (0.255 ml, 1.5 mmol) in 20 ml DCM for 2.5 hours. The resin was washed with DMF (2 x 30 ml) and dichloromethane (3×30 ml) and dried in vacuum.

Cleavage of the peptide from the resin was carried out using a solution of phenol (1.5 g), water (1.5 ml) and TIPS (0.6 ml) in TFA (QSP 30 ml) for 2.5 hours at room temperature. The resin was filtered and washed with 2×10 ml TFA. The combined filtrates were transferred to a 250 ml round bottom flask and partially concentrated in vacuo at T<30° C., the peptide was precipitated by adding 100 ml of ice-cold MTBE and centrifuged at 3600 rpm. within 30 minutes.

The centrifuged sediment was then washed with ice-cold diethyl ether and centrifuged. This process was repeated three times. 720 g of crude peptide were obtained. Purification was accomplished using Purification System B in 3 injections of 240 mg each. Fractions containing pure desired peptide were lyophilized. The trifluoroacetate salt peptide was obtained as a white solid.

m=72 mg (3.6%)

UPLC/MS:

RT: 5.86 min. (analytical condition A), 98% purity (UV)

Observed mass, mass/charge (ion type): 1463.9 (M+3H); 1098.2 (M+4H); 878.7 (M+5H).

2.D. Synthesis of peptide having SEQ ID NO: 6

A batch of resin obtained in 2.A., corresponding to 0.1 mmol Fmoc-Lys(Ac)-NH2, was placed in the reactor of the CEM Liberty Blue microwave peptide synthesis device. Peptide synthesis was performed using 0.5 M DIC/1 M Oxyma in DMF.

All amino acids were double-coupled at 90°C as above, with the exception of aminoisobutyric acid at position 21 and serine at position 29, which were triple-coupled at 90°C for 2 minutes. Fmoc-Lys(ivDde)-OH was used at position 25.

At the end of peptide assembly, the resin was transferred to a 20 ml polypropylene syringe and the peptide was N-terminal acetylated with acetic anhydride (95 µl, 1 mmol) and DIPEA (174 µl, 1 mmol) in DMF (10 ml) for 20 minutes, repeating the cycle twice.

The ivDde protecting group on the side chain of lysine 25 was then removed by stirring with 10 mL of a 5% w/v solution. hydrazine in DMF for 20 min. as many times as necessary until no more detectable starting material was detected after an aliquot of the resin was digested and analyzed by UPLC/MS. When deprotection was judged to be complete, the resin was washed with DMF (5×10 ml).

Two TTDS spacer units were introduced by single coupling by performing the following procedure twice: A solution of Fmoc-TTDS-OH (163 mg, 0.3 mmol), HOAt (42 mg, 0.3 mmol) and DIC (77 μl) was added to the resin , 0.5 mmol) in 7 ml DMF. The syringe was stirred on a stirring table for 18 hours. The reaction was monitored using the Kaiser test. If necessary, a double combination was performed. The resin was washed with DMF (2×10 ml). Then 10 ml of 20% v/v was added to the resin. piperidine in DMF. The syringe was mixed on a mixing table for 20 minutes. This deprotection procedure was repeated a second time and the resin was washed with DMF (2 x 10 ml) and dichloromethane (3 x 10 ml).

Three gamma-glutamic acid spacers were introduced by performing a double coupling of each Fmoc-Glu-OtBu. Thus, the following procedure was applied three times.

A solution of (4S)-5-tert-butoxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxopentanoic acid (Fmoc-Glu-OtBu) (127 mg, 0.3 mmol), HOAt (42 mg, 0.3 mmol) and DIC (77 µl, 0.5 mmol) in 7 ml DMF. The syringe was stirred on a stirring table for 18 hours. The reaction was monitored using the Kaiser test. The resin was washed with DMF (2×10 ml). Then 10 ml of 20% v/v was added to the resin. piperidine in DMF. The syringe was mixed on a mixing table for 20 minutes. This deprotection procedure was repeated a second time and the resin was washed with DMF (3 x 10 ml) and dichloromethane (3 x 30 ml).

Finally, the peptide was acylated with stearoyl chloride (62 mg, 0.2 mmol) and DIPEA (54 μl, 0.3 mmol) in 5 ml DCM for 2.5 h. The resin was washed with DMF (2 x 30 ml) and dichloromethane (3×30 ml) and dried in vacuum.

Cleavage of the peptide from the resin was carried out using a solution of phenol (0.5 g), water (0.5 ml) and TIPS (0.2 ml) in TFA (QSP 10 ml) for 2.5 hours at room temperature. The resin was filtered and washed with 2×4 ml TFA. The combined filtrates were transferred to a 100 ml round bottom flask and partially concentrated in vacuo at T<30° C. and the peptide was precipitated by adding 50 ml of ice-cold MTBE and centrifuged at 3600 rpm. within 30 minutes.

The centrifuged sediment was then washed with ice-cold diethyl ether and centrifuged. This process was repeated three times. 240 g of crude peptide were obtained. Purification was carried out using purification system B and fractions containing pure desired peptide were lyophilized. The trifluoroacetate salt peptide was obtained as a white solid.

m=38 mg (8%)

UPLC/MS:

RT: 5.40 min. (analytical condition A), 97% purity (UV)

Observed mass, mass/charge (ion type): 1376.1 (M+3H); 1032.0 (M+4H); 826.0 (M+5H).

2.E. Synthesis of peptide having SEQ ID NO: 20

This compound was prepared according to the same procedure as used in Example 2.D, except that three TTDS were introduced into the lysine 25 side chain.

Thus, from 250 mg of the resin obtained in 2.A., corresponding to 0.1 mmol Fmoc-Lys(Ac)-NH2, a white solid was obtained.

m=20 mg (4.5%)

UPLC/MS:

RT: 5.44 min. (analytical condition A), 99% purity (UV)

Observed mass, mass/charge (ion type): 2215.0 (M+2H); 1476.8 (M+3H); 1107.9 (M+4H); 886.7 (M+5H).

2.F. Synthesis of peptide having SEQ ID NO: 22

This compound was prepared according to the same procedure as used in Example 2.B, except that at position 25 (X ₂₅ ) Fmoc-Lys(Dde)-OH was used instead of Fmoc-Lys(Dde)-OH.

Thus, 250 mg of the resin obtained in 2.A., corresponding to 0.1 mmol Fmoc-Lys(Ac)-NH2, was treated as in 2.B. to the stage of N-terminal acetylation.

The Aloc group on the Lys25 side chain was removed by adding to the resin under argon a solution of 1 ml (8.33 mmol) phenylsilane in 2 ml degassed DCM and a solution of 10 mg (25.96 µmol) tetrakis(triphenylphosphine)palladium in 4 ml DCM . The resin was shaken on a mixing table for 60 min. and the reaction medium was replaced twice with fresh reagents and shaken for 60 min each time.

When the reaction was complete, the resin was washed with dichloromethane, 1% DIEA in DMF, 5% diethyldithiocarbamate in DMF, DMF, 10% DIEA in DMF, DMF and dichloromethane (3 times each).

Three PEG ₂ DGA spacer units were introduced in a single combination by performing the following procedure three times. A solution of Fmoc-PEG ₂ DGA-OH (170 mg, 0.3 mmol) in 8 ml DCM was added to the resin, followed by the addition of HOAt (0.5 ml, 0.6 ml solution in DMF, 0.3 mmol) and DIC (100 µl, 0.642 mmol). The syringe was stirred on a stirring table for 18 hours. The reaction was monitored using the Kaiser test. The resin was washed with DMF (2×10 ml). Then 10 ml of 20% v/v was added to the resin. piperidine in DMF. The syringe was mixed on a mixing table for 20 minutes. This deprotection procedure was repeated a second time and the resin was washed with DMF (2 x 30 ml) and dichloromethane (3 x 30 ml).

Three gamma-glutamic acid spacers were introduced by performing a double coupling of each Fmoc-Glu-OtBu. Thus, the following procedure was applied three times.

A solution of (4S)-5-tert-butoxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxopentanoic acid (Fmoc-Glu-OtBu) (0.13 g, 0.3 mmol) in 8 ml DMF, followed by the addition of HOAt (0.5 ml 0.6 ml solution in DMF, 0.3 mmol) and DIC (0.1 ml, 0.6 mmol). The syringe was mixed on a stirring table for 4 hours. The resin was washed with DMF (2x20 ml) and the combination was repeated a second time. The reaction was monitored using the Kaiser test. The resin was washed with DMF (2×10 ml). Then 10 ml of 20% v/v was added to the resin. piperidine in DMF. The syringe was mixed on a mixing table for 20 minutes. This deprotection procedure was repeated a second time and the resin was washed with DMF (3 x 30 ml) and dichloromethane (3 x 30 ml).

Finally, the peptide was acylated with palmitic acid (80 mg, 0.3 mmol), HOAt (0.5 mL 0.6 M solution in DMF, 3 mmol) and DIC activation (0.1 mL, 6 mmol) in DMF ( 10 ml) for 2.5 hours. The resin was washed with DMF (2x30 ml) and dichloromethane (3x30 ml) and dried in vacuum.

Cleavage of the peptide from the resin was carried out using a solution of phenol (0.5 g), water (0.5 ml) and TIPS (0.25 ml) in TFA (QSP 10 ml) for 2.5 hours at room temperature. The resin was filtered and washed with 2x5 ml TFA. The combined filtrates were transferred to a 250 ml round bottom flask and partially concentrated in vacuo at T<30° C. and the peptide was precipitated by adding 100 ml of ice-cold MTBE and centrifuged at 3600 rpm. within 30 minutes.

The centrifuged sediment was then washed with ice-cold diethyl ether and centrifuged. This process was repeated three times. 220 g of crude peptide were obtained.

Purification was carried out using purification system B. Fractions containing pure desired peptide were lyophilized. The trifluoroacetate salt peptide was obtained as a white solid.

m=37 mg (8%)

UPLC/MS:

RT: 4.99 min. (analytical condition A), 99% purity (UV)

Observed mass, mass/charge (ion type): 2205.2 (M+2H); 1470.5 (M+3H); 1103.1 (M+4H); 882.7 (M+5H).

2.G. results

Results obtained by the peptides of the present invention under SEQ ID NO:

1-32, 34-37, 39, 44, 45, 47-49, 51 and 54-97 are listed in the following Table 1.

SEQ ID NO Minimum UPLC Retention Time (Conditions) Observed mass Monoisotopic mass Ion type M+5H M+4H M+3H M+2H 1 3.81(C) 881.3 1101.3 1467.7 4397.54 2 3.85(C) 861.9 1077.2 1436.3 4301.47 3 4.98(A) 873.1 1091.1 1454.5 2181.5 4358.53 4 5.02(A) 820.5 1025.3 1366.7 2049.4 4095.36 5 4.82(A) 815.7 1019.3 1358.8 2037.3 4071.28 6 5.40(A) 826.0 1032.0 1376.1 2063.8 4123.39 7 5.86(A) 878.7 1098.2 1463.9 4386.56 8 4.83(A) 807.8 1009.5 1345.7 2018.3 4032.27 9 4.97(A) 786.9 983.3 1310.7 1965.7 3927.30 10 4.90(A) 838.5 1047.8 1396.8 2094.8 4185.39 eleven 5.03(A) 880.9 1100.9 1467.5 2200.9 4397.54 12 4.98(A) 870.5 1087.9 1450.2 2174.9 4345.5 13 4.99(A) 870.3 1087.6 1449.8 2174.7 4344.5 14 4.96(A) 870.3 1087.6 1449.8 4344.5 15 5.00(A) 869.9 1087.1 1449.2 2173.3 4342.5 16 4.92(A) 809.9 1012.1 1349.1 2023.2 4042.33 17 5.00(A) 817.6 1021.8 1362.1 2042.6 4081.34 18 4.73(A) 829.3 1036.1 1381.2 4138.40 19 4.88(A) 786.6 983.0 1310.0 1965.3 3926.21 20 5.44(A) 886.7 1107.9 1476.8 2215.0 4425.57 21 5.27(A) 821.4 1026.3 1369.1 2051.6 4099.31 22 4.99(A) 882.7 1103.1 1470.5 2205.2 4406.5 23 5.24(A) 870.1 1087.4 1449.5 2173.8 4343.52 24 5.25(A) 876.9 1095.1 1460.8 2190.8 4377.50 25 5.17(A) 873.1 1091.4 1454.5 2181.3 4358.49 26 5.24(A) 813.4 1016.5 1355.0 2032.1 4060.3 27 4.97(A) 878.7 1098.1 1463.8 2194.9 4386.54 28 4.97(A) 875.9 1094.6 1459.1 2188.2 4372.55 29 5.00(A) 875.9 1094.6 1459.2 2188.3 4372.54 thirty 5.44(A) 886.5 1107.9 1476.9 4425.57 31 5.07(A) 886.5 1107.9 1476.8 4425.5 32 5.42(A) 888.3 1110.3 1479.8 2219.5 4434.5 34 5.45(A) 818.2 1022.5 1363.4 4084.4 35 5.03(A) 877.8 1096.8 1462.4 2192.9 4381.5 36 4.96(A) 870.1 1087.6 1450.1 2174.3 4344.5 37 5.1(A) 883.3 1103.6 1471.5 2207.4 4410.5 39 5.20(A) 890.1 112.8 1483.1 2224.6 4444.52 44 4.80(A) 877.8 1097.1 1462.8 4383.5 45 4.81(A) 836.6 1045.7 1393.7 2090.6 4177.3 47 4.85(A) 864.6 1080.3 1440.4 2160.5 4316.5 48 9.23(D) 864.6 1080.6 1440.8 2160.2 4316.5 49 9.00 (D) 864.6 1080.6 1440.4 2160.3 4316.5 51 5.38(A) 912.3 1140.1 1519.8 2279.2 4554.6 54 5.41(A) 851.8 1064.5 1419.1 2128.2 4252.4 55 5.03(A) 892.1 1114.8 1486.1 4453.6 56 5.42(A) 876.1 1094.8 1459.5 4373.5 57 4.90(A) 880.9 1100.9 1467.1 2201.2 4316.5 58 5.48(A) 946.8 1183.3 1577.5 4727.7 59 5.44(A) 972.7 1215.6 1620.5 4856.8 60 5.34(A) 818.2 1022.5 1363.0 2044.0 4084.4 61 5.41(A) 878.4 1098.1 1463.7 2195.1 4386.6 62 5.34(A) 906.6 1133.1 1510.5 4526.6 63 4.98(A) 886.3 1107.6 1476.5 4424.6 64 4.8(A) 891.9 1114.6 1485.9 4452.6 65 4.97(A) 892.2 1115.1 1486.4 2228.7 4454.6 66 4.97(A) 897.5 1121.7 1495.2 4480.6 67 4.98(A) 886.3 1107.8 1476.8 4425.5 68 5.05(A) 880.9 1100.9 1467.5 4397.5 69 5.06(A) 886.5 1107.8 1476.8 4425.5 70 9.29(D) 886.5 1107.8 1476.8 4425.6 71 4.84(A) 860.9 1076.3 1434.4 4298.5 72 7.86(D) 875.4 1094.1 1458.5 2187.4 4370.5 73 4.87(A) 866.5 1082.8 1443.4 4325.5 74 5.12(A) 946.9 1183.4 1577.5 4727.8 75 5.28(A) 952.4 1190.6 1590.9 4755.7 76 5.28(A) 884.2 1105.1 1473.1 4414.5 77 5.20(A) 944.5 1180.7 1573.8 4716.7 78 4.09(A) 933.5 1166.7 1554.9 4660.7 79 4.66(A) 878.5 1098.1 1463.5 4385.6 80 4.90(A) 898.8 1123.5 1497.7 4487.5 81 4.84(A) 884.5 1105.3 1473.4 2210.1 4415.6 82 4.90(A) 883.7 1104.4 1472.1 4411.6 83 4.71(A) 886.5 1107.6 1476.7 2214.4 4424.6 84 5.12(A) 878.7 1097.9 1463.8 2195.1 4386.6 85 4.98(A) 894.7 1118.6 1490.8 4467.6 86 5.14(A) 873.1 1091.1 1454.4 2181.6 4358.5 87 4.81(A) 875.7 1094.6 1459.1 2187.7 4372.5 88 4.82(A) 873.1 1090.9 1454.2 2181.3 4358.5 89 4.28(A) 732.4 878.7 1098.2 1436.9 4386.5 90 4.82(A) 870.1 1087.3 1449.5 2174.2 4344.5 91 4.89(A) 887.7 1109.6 1479.2 2218.9 4432.5 92 4.20(A) 895.7 1119.4 1492.2 4471.5 93 4.83(A) 878.5 1097.7 1463.9 2194.9 4386.5 94 4.84(A) 878.2 1097.5 1463.3 2194.5 4384.6 95 4.40(A) 867.8 1084.2 1445.3 2167.9 4330.5 96 4.24(A) 859.0 1073.5 1431.3 2146.5 4288.5 97 3.77(A) 884.9 1105.9 1474.2 4417.5

Table 1

Condition A is as follows.

- Column: Acquity Peptide CSH, C18, 130Å, 2.1×100 mm, 1.7 µm;

- column temperature: 50°C; flow rate=0.6 ml/min;

- solvent A: 0.1% TFA in H ₂ O;

- solvent B: 0.1% TFA in CH ₃ CN;

- gradient: from 0 to 1 min. B=2%, from 1 to 7 min. B=2% to 70%, 7 to 8 min. B=70% to 100%;

- UV detector: wavelength: 220 nm; MS collection: ESI+ from 200 to 3000 amu.

Condition B is as follows.

- Column: Acquity BEH C18, 130Å, 2.1×50 mm, 1.7 µm;

- column temperature 60°C; flow rate 0.6 ml/min;

- solvent A: 0.05% TFA in H ₂ O;

- solvent B: 0.05% TFA in CH ₃ CN;

gradient: 0 to 1 min. B=2%, from 1 to 16 min. B=2% to 100%, 16 to 17 min.

B= 100%;

UV detector: wavelength: 220 nm; MS collection: ESI+ from 200 to 3000 amu.

Condition C is as follows.

- Column: ACQUITY BEH C4, 130Å, 2.1×50 mm, 1.7 µm;

- column temperature 45°C; flow rate: 0.4 ml/min;

- solvent A: 0.1% TFA in H ₂ O;

- solvent B: 0.05% TFA in CH ₃ CN;

gradient: 0 to 1 min. B=30%, from 1 to 5 min. B=30% to 50%, 5 to 6 min.

B=80%

UV detector: wavelength: 220 nm; MS collection: ESI+ from 200 to 3000 amu.

Condition D is as follows.

- Column: Acquity Peptide CSH, C18, 130Å, 2.1×150 mm, 1.7 µm;

- column temperature: 60°C; flow rate=0.4 ml/min;

- solvent A: 0.1% TFA in H ₂ O;

- solvent B: 0.1% TFA in CH ₃ CN;

- gradient: from 0 to 1 min. B=2%, from 1 to 14 min. B=2% to 70%, 14 to 16 min B=70% to 100%;

- UV detector: wavelength: 220 nm; MS collection: ESI+ from 200 to 3000 amu.

The following peptides of the present invention can be prepared accordingly as described above. SEQ ID NOs 33, 38, 40, 41, 43, 46, 50, 52 and 53.

Example 3: Analysis of Peptides of the Present Invention on RXFP1 Receptors in vitro (OVCAR5 cAMP assay)

A. Method

OVCAR5 cells expressing endogenous RXFP1 were used to test the RXP1 agonistic properties of the peptides of the present invention, and in particular those of SEQ ID NO: 1-97.

Because RXFP1 is a G protein-coupled GPCR, cAMP was used to detect RXFP1 activation.

Isobutylmethylxanthine (IBMX) was used to inhibit phosphodiesterase activity, facilitating cAMP measurements. HTRF (homogeneous time-resolved fluorescence) technology was used to detect cAMP due to its high sensitivity.

Thus, OVCAR5 was grown in regular medium (RPMI) containing 10% fetal calf serum (FCS) and 1% antibiotics (penicillin/streptomycin).

Before experiments, cells were detached using accutase and incubated for 40 min at 37°C with 1 mM (3-isobutyl-1-methylxanthine) IBMX.

Cells were then distributed into black 384-well plates containing increasing concentrations of different peptides in a fixed volume of medium (without FCS).

After incubation for 30 min. at 37°C in a humidified incubator in 5% CO ₂ the reaction was stopped by adding a fixed volume of solution containing lysis buffer and cAMP-D2 (cAMP labeled with d2 dye) and the europium-linked cAMP antibody used to detect cAMP.

The experimental data were recorded on a fluorimeter capable of measuring using HTRF. Activation curves were obtained by plotting intracellular cAMP content versus log10 compound concentration.

The 50% activation concentration ( _EC50 ) was calculated by nonlinear regression using a sigmoidal dose-response equation (variable slope) using Prism 5 software.

Emax% was determined as the maximum intracellular cAMP content for the test compound (the upper limit of the cAMP concentration curve) divided by the maximum intracellular cAMP content for relaxin H2 determined in the same test case and multiplied by 100.

Emax% = 100 x [cAMP _{tested conn.} ] / [cAMP _H2-Rlx ]

B. Results

The results obtained by the peptides of the present invention are presented in the following Table 2.

SEQ ID NO OVCAR 5 cells (cAMP) EC50 (nM) EMax 1 1.50 99% 2 2.40 99% 3 0.34 97% 4 1.50 89% 5 9.10 85% 6 0.27 95% 7 0.07 95% 8 1.86 92% 9 0.70 93% 10 0.79 95% eleven 0.83 93% 12 0.93 90% 13 2.12 91% 14 3.20 90% 15 2.10 85% 16 6.80 88% 17 4.60 91% 18 1.54 92% 19 11.5 94% 20 0.15 96% 21 0.65 93% 22 1.00 92% 23 11.1 92% 24 36.4 100% 25 28.7 100% 26 0.43 96% 27 1.80 98% 28 0.62 88% 29 1.60 88% thirty 0.21 89% 31 0.19 94% 32 0.10 97% 34 0.14 90% 35 2.33 91% 36 3.60 93% 37 5.60 98% 39 8.70 93% 42 1.50 84% 44 2.2 97% 45 0.45 96% 47 0.64 95% 48 0.45 96% 49 0.19 97% 51 0.10 98% 54 0.16 96% 55 0.18 93% 56 0.15 91% 57 0.44 98% 58 0.08 98% 59 0.09 99% 60 0.15 95% 61 0.10 97% 62 0.60 98% 63 1.45 97% 64 0.52 95% 65 1.19 95% 66 6.31 93% 67 0.48 95% 68 0.88 98% 69 0.78 97% 70 1.34 94% 71 0.36 95% 72 0.56 91% 73 0.20 95% 74 0.54 94% 75 0.19 97% 76 0.18 96% 77 0.11 98% 78 0.18 99% 79 0.45 95% 80 0.63 93% 81 0.16 98% 82 0.54 95% 83 0.25 94% 84 0.10 95% 85 0.30 92% 86 0.30 95% 87 0.10 96% 88 0.17 96% 89 0.10 97% 90 0.14 97% 91 0.09 97% 92 0.10 99% 93 0.77 86% 94 1.74 88% 95 1.80 91% 96 0.88 92% 97 0.29 98%

table 2

The peptides of the present invention appear to have very interesting RXP1 agonistic properties and are very effective in binding and activating RXFP1.

In addition, they are all significantly and unexpectedly superior to prior art peptides when it comes to activating the RXFP1 receptor.

The same experiment was carried out with the prior art peptides (WO2015/157829) known as B7-33 C11.23S, AcB7-33 C11.23S and KKKK(AcB7-29 C11.23S).

The following EC ₅₀ results were obtained for these three peptides.

Name cAMP assay in OVCAR 5 cells EC50 (nM) Emax B7-33 C11.23S 1641 90% AcB7-33 C11.23S 929 70% KKKK(AcB7-29 C11.23S) 206 84%

Table 3

As shown above, the peptides of the present invention have very interesting agonistic properties towards RXFP1 and are very effective in activating RXFP1. In addition, they are all significantly and unexpectedly superior to prior art peptides.

Example 4 Solubility Analysis of Peptides of the Present Invention in Buffer

A. Method

Before testing a batch of peptide for solubility, its purity was determined (HPLC-UV).

Environment for research.

Phosphate buffer 50 mM, pH 6.5: 15.9 ml Na ₂ HPO ₄ 0.1 M (Carlo Erba 480087) + 34.1 ml NaH ₂ PO ₄ 0.1 M (Carlo Erba 480141) + H ₂ O MilliQ QSP 100 ml

Phosphate buffer 50 mM, pH 7.4: 40.5 ml Na ₂ HPO ₄ 0.1 M (Carlo Erba 480087) + 9.5 ml NaH ₂ PO ₄ 0.1 M (Carlo Erba 480141) + H ₂ O MilliQ QSP 100 ml

Acetate buffer 50 mM pH 4.5: 100% solution of 0.75 g C ₂ H ₃ CO ₂ Na, 3 H ₂ O (Sigma S7545) + 0.35 ml CH ₃ CO ₂ H dissolved in Millipore water, adjusted to pH with diluted (1:1) CH ₃ CO ₂ H and diluted to 250 ml with Millipore water.

In a 4 mL Eppendorf vial, an accurately weighed sample of compound was diluted in assay media to obtain a target concentration of 2, 6, or 10 mg/mL of pure compound. Vials with samples were shaken (rotating shaker) for ~19 hours. Aliquots of 300 μl were filtered through a Millipore "Solvinert" plate (0.45 μm - hydrophilic PTFE). Solubility was then determined by comparing the injection of 0.2 pL of filtrate with the UV peak areas obtained from a 1.2 mg/mL peptide stock solution in DMSO (based on % purity) at various injection volumes ranging from 0.2-2 pL .

Analysis:

pH was measured using a microelectrode

HPLC terms:

Waters Acquity UPLC System with DAD Detector

Column: Waters Peptide CSH C18 Column (130Å; 1.7 µm; 50*2.1 mm)

Column temperature: 60°C

Flow: 0.3 ml/min.

Full loop fill (approximately 5 µl) - overflow factor 5

Light and strong rinse solution: H2O/ACN (75/25; v/v); solution for flushing valves: H2O/IsOH (95/5; v/v). Mobile phase:

solvent A: 0.05% TFA in H ₂ O; Solvent B: 0.035% TFA in CH3CN.

Gradient: 0 to 12 min. B=2% to 60%, 12 to 14 min. B= 60% to 100%; Column wash 100% B 1 min., column equilibrated 2% B 2.5 min.

UV detector: wavelength: 220 nm.

B. Results

The solubility results obtained are presented in the following Table 4.

SEQ ID NO Solubility in acetate buffer
pH 4.5* Solubility in phosphate buffer, pH 7.4* 3 11.1 mg/ml 11.5 mg/ml 4 9.63 mg/ml 7.71 mg/ml 5 6.24 mg/ml 6.41 mg/ml 7 11.45 mg/ml 11.83 mg/ml 13 N. d. 7.68 mg/ml 16 6.33 mg/ml 6.72 mg/ml 17 9.22 mg/ml 6.81 mg/ml 18 6.75 mg/ml 6.58 mg/ml 20 9.34 mg/ml 9.95 mg/ml 21 6.28 mg/ml 6.59 mg/ml 23 0.55 mg/ml 6.77 mg/ml 24 0.28 mg/ml 6.93 mg/ml 25 6.58 mg/ml 6.75 mg/ml 26 6.68 mg/ml 6.76 mg/ml 44 11.07 mg/ml 10.72 mg/ml 55 9.26 mg/ml 8.84 mg/ml 70 8.24 mg/ml 9.68 mg/ml 71 8.28 mg/ml 8.77 mg/ml 72 8.25 mg/ml 8.72 mg/ml 74 7.39 mg/ml 8.47 mg/ml 75 8.58 mg/ml 9.56 mg/ml

Table 4. *Target solubility: 10.0 mg/ml

The same experiment was carried out with the prior art peptides (WO2015/157829) known as B7-33 C11.23S, AcB7-33 C11.23S and KKK(AcB7-29 C11.23S).

The following solubility results were obtained for these three peptides.

Name Solubility in acetate buffer, pH 4.5** Solubility in phosphate buffer, pH 7.4** B7-33 C11.23S 1.9 mg/ml 0.014 mg/ml AcB7-33 C11.23S 1.54 mg/ml <0.001 mg/ml KKKK(AcB7-29 C11.23S) 2.3 mg/ml 0.177 mg/ml

Table 5

** Target solubility: 2.0 mg/ml

The peptides of the present invention exhibit improved solubility compared to prior art compounds. This property allows for a greater range of concentrations when preparing solutions for injection, thus expanding in vivo dose ranges.

Example 5: Analysis of the stability of peptides in rat or human plasma or blood

A. Method

Before testing a batch of peptide for stability in blood plasma (or blood), its purity was determined (HPLC-UV).

Environment for research.

Rat and human blood plasma: anticoagulant sodium or lithium heparin.

Rat and human blood: anticoagulant sodium or lithium heparin.

Stock solution:

100 μM solution of the test compound in 50 mM phosphate buffer, pH 7.4.

950 μl of blood plasma (or blood) was pre-incubated for 5 min. at 37°C. 50 μl of compound stock solution was added. Final compound concentration=5 µM. At each time point, the solution was vortex-mixed and 150 μl of blood plasma (or blood) was transferred to an Eppendorf. Analysis at time points 0-1 and -4 hours was carried out in duplicate for each species.

After incubation, 150 μl of blood plasma (or blood) was extracted with 600 μl of acetonitrile containing 1% TFA. The mixture was then vortex-mixed and centrifuged for 10 minutes. at 14600 rpm. 200 μl of the supernatant was dried under N ₂ atmosphere. The sample was then reconstituted in 200 µl H ₂ O/CH ₃ CN 98/2 + 0.1% FA + 50 ng/ml Labetalol and analyzed using the analytical system used in solubility and stability studies.

To determine the amount of peptide remaining, the peak areas of the target compound at t0 and at each time point were compared to obtain "% peptide remaining" based on the equation:

% peptide remaining = [(peptide peak area at time) x 100]/peptide peak area at t0. Stability was expressed as “% peptide remaining.”

Eligibility Criteria. Test compounds were considered stable if the accuracy was ~15% and the recovery was in the range of 85–115%.

B. Results

The results obtained for stability in plasma and blood are presented in the following Table 6.

SEQ ID NO Stability in human plasma Stability in rat plasma % remaining % remaining T=0 1 hour 4 hours T=0 1 hour 4 hours 3 99 95 100 98 100 87 3* 100* 95* 95* 100* 95* 84* 4 100 100 100 100 100 59 4* 100* 100* 99* 100* 102* 86* 6 97 92 91 97 94 N. d. 7 92 94 87 77 100 66 13 100 91 89 89 100 N. d. 20 87 100 83 100 100 N. d.

Table 6. * Stability in blood

The same experiment was carried out with the prior art peptides (WO2015/157829) known as B7-33 C11.23S, AcB7-33 and KKKK(AcB7-29 C11.23S).

The following plasma stability results were obtained for these three peptides.

Name Stability in human plasma Stability in rat plasma % remaining % remaining T=0 1 hour 4 hours T=0 1 hour 4 hours B7-33 C11.23S 100 18 3 100 15 2 Ac B7-33 100 67 18 100 16 2 KKKK(AcB7-29 C11.23S) 100 41 31 100 23 14

Table 7

The peptides of the present invention appear to be more stable in plasma and/or blood than the prior art compounds.

Example 6. Determination of pharmacokinetics (PK) of peptides after administration to rats in vivo .

A. Method.

Before testing, the peptide batch was determined for its purity (HPLC-UV). The dose was adjusted for the presence of salts, solvent, and purity.

Bioanalytical screening method for peptide quantitation in rats.

Sprague Dawley rats were administered the test peptide at a dose of 1 mg/kg intravenously (i.v.) or 3 mg/kg subcutaneously (s.c.) as a solution in PBS (0.2 mg/ml and 0.6 mg/ml, respectively).

Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, 48 and 72 hours (i.v. route) and 0.25, 0.5, 1, 2, 4, 6. 8, 10, 24, 48 and 72 hours (s.c. route) after administration.

Blood plasma samples were analyzed after protein precipitation by liquid chromatography/mass spectrometry (LC/MS).

PK parameters and half-life were calculated using Phoenix 64 (WinNonlin 6.4) - Pharsight (CertaraTM) (non-compartmental model). Values below the limit of quantitation (BLQ) were replaced by zero for subsequent PK calculations and analysis.

B. Results.

The results obtained for the PK parameters are presented in the following Table 8.

The following abbreviations are used.

T½: in vivo half-life, the time required for the plasma concentration of the test compound to decrease by half during a PK experiment.

C0: extrapolated plasma concentration of test compound at time t=0 (i.v. path).

Cmax: maximum plasma concentration of the test compound at a specified time point (s.c. pathway).

Tmax: Time point at which Cmax was reached.

F%: bioavailability s.c. vs. i.v., dose-adjusted area under the curve (AUC) s.c. pathway divided by AUC i.v.

SEQ ID NO PK in rat, 1 mg/kg i.v. PK in rat, 3 mg/kg s.c. T½ (hours) C0 (µM) Cmax (µM) Tmax (h) F% 3 7.8 3.2 2.3 8 83 4 8.71 2.75 1.99 8 69 6 5.59 5.17 2.71 8 72 7 6.34 4.16 1.53 10 61 20 5.13 3.09 1.99 10 80 55 4.89 4.91 2.07 6 65

Table 8

The same experiment was performed with relaxin H2.

Compound PK in rat, 1 mg/kg i.v. T½ (hours) C0 (µM) Relaxin H2 0.46 0.87

Table 9

Compared to relaxin H2, the selected peptides of the present invention demonstrate improved pharmacokinetic parameters. In particular, the in vivo half-life in rats varies from 4 hours to 9 hours. Such peptides could then maintain their effectiveness for a longer period of time, allowing for once-daily administration by the intravenous or subcutaneous route.

List of sequences

SEQ ID NO: 1

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 2

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Aib-RAK(Ac)-NH ₂

SEQ ID NO: 3

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 4

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 5

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ -PEG ₂ -PEG ₂ -PEG ₂ -gE-gE-gE-Palm)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 6

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-gE-gE-gE-Stea)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 7

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Stea)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 8

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ -PEG ₂ -PEG ₂ -PEG ₂ -gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 9

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 10

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-gE-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 11

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 12

Ac-LEGREKVRA-Cit-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 13

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFSKRAK(Ac)-NH ₂

SEQ ID NO: 14

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STF-Dser-KRAK(Ac)-NH ₂

SEQ ID NO: 15

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STF-Aib-KRAK(Ac)-NH ₂

SEQ ID NO: 16

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-gE-gE-gE-Palm)-STFS-Dlys-RAK(Ac)-NH ₂

SEQ ID NO: 17

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-gE-gE-gE-Palm)-STWS-Dlys-RAK(Ac)-NH ₂

SEQ ID NO: 18

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-gE-gE-gE-Palm)-STWS-Dlys-RKK(Ac)-NH ₂

SEQ ID NO: 19

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ -PEG ₂ -PEG ₂ -gE-gE-gE-Palm)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 20

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Stea)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 21

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ -PEG ₂ -PEG ₂ -PEG ₂ -gE-gE-gE-Stea)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 22

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ DGA-PEG ₂ DGA-PEG ₂ DGA-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 23

Ac-LEGRELVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 24

Ac-LEGREFVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 25

Ac-LEGREQVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 26

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ -PEG ₂ -PEG ₂ -PEG ₂ -gE-gE-gE-Stea)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 27

Ac-LEGRERVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 28

Ac-LEGRE-Hly-VRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 29

Ac-LEGREKVR-Aib-K(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 30

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Stea)-STWS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 31

Ac-LEGRERVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RRK(Ac)-NH ₂

SEQ ID NO: 32

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ DGA-PEG ₂ DGA-PEG ₂ DGA-gE-gE-gE-Stea)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 33

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 34

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-gE-gE-gE-Stea)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 35

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STW-Aib-KRAK(Ac)-NH ₂

SEQ ID NO: 36

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Dlys-RAK(Ac)-NH ₂

SEQ ID NO: 37

Ac-LEGRELVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RRK(Ac)-NH ₂

SEQ ID NO: 38

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ -PEG ₂ -PEG ₂ -gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 39

Ac-LEGREFVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RRK(Ac)-NH ₂

SEQ ID NO: 40

Ac-LEGREQVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RRK(Ac)-NH ₂

SEQ ID NO: 41

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ DGA-PEG ₂ DGA-PEG ₂ DGA-gE-gE-gE-Palm)-STWS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 42

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ -PEG ₂ -PEG ₂ -PEG ₂ -gE-gE-gE-Palm)-STWS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 43

Ac-LEGRE-Hly-VRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Stea)-STWS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 44

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STW-Dser-KRAK(Ac)-NH ₂

SEQ ID NO: 45

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ -PEG ₂ -PEG ₂ -PEG ₂ -PEG ₂ -gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 46

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ -PEG ₂ -PEG ₂ -PEG ₂ -PEG ₂ -gE-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)- NH ₂

SEQ ID NO: 47

Ac-LEGREKVRAKI-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 48

Ac-LEGREKVRAQI-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 49

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK-NH ₂

SEQ ID NO: 50

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ DGA-PEG ₂ DGA-PEG ₂ DGA-gE-gE-gE-Stea)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 51

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-gE-Stea)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 52

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-Stea)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 53

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(PEG ₂ DGA-PEG ₂ DGA-PEG ₂ DGA-gE-gE-gE-gE-Stea)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 54

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-gE-gE-gE-gE-Stea)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 55

Ac-LEGRERVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RRK(Ac)-NH ₂

SEQ ID NO: 56

Ac-LEGREKVRA-Cit-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Stea)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 57

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Hly-RAK(Ac)-NH ₂

SEQ ID NO: 58

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-TTDS-gE-gE-gE-Stea)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 59

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-TTDS-gE-gE-gE-Stea)-STFS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 60

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-gE-gE-gE-Stea)-STFS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 61

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Stea)-STFS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 62

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-gE-Palm)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 63

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-SQWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 64

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-SRWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 65

Ac-LEGREKVRK(Ac)-QI-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 66

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWK(Ac)-Aib-RAK(Ac)-NH ₂

SEQ ID NO: 67

Ac-LEGRERVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 68

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RK(Ac)-K-NH ₂

SEQ ID NO: 69

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RK(Ac)-R-NH ₂

SEQ ID NO: 70

Ac-LEGREKVRAK(Ac)-I-Aib-IEGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 71

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RAK-NH ₂

SEQ ID NO: 72

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STF-Aib-RRAK(Ac)-NH ₂

SEQ ID NO: 73

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-SKWS-Aib-RAK-NH ₂

SEQ ID NO: 74

Ac-LEGREKVRAK(Ac)-I-Aib-IEGK(TTDS-TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 75

Ac-LEGRERVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RRK(Ac)-NH ₂

SEQ ID NO: 76

Ac-LEGRERVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Aib-RRK(Ac)-NH ₂

SEQ ID NO: 77

Ac-LEGRERVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Aib-RRK(Ac)-NH ₂

SEQ ID NO: 78

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 79

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-SKFS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 80

Ac-LEGRERVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-ST-Trp(5-Cl)-S-Aib-RRK(Ac)-NH ₂

SEQ ID NO: 81

Ac-K(Ac)-EGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 82

Ac-LEGREKVR-Aib-K(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STWS-Aib-RAK(Ac)-NH ₂

SEQ ID NO: 83

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-SKWS-Aib-RKK(Ac)-NH ₂

SEQ ID NO: 84

Ac-LEGREKVRAK(Ac)-I-Aib-IEGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 85

Ac-LEGRERVR-Aib-K(Ac) I Aib Aib EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm) STWS Aib RRK(Ac)-NH ₂

SEQ ID NO: 86

Ac-Aib-EGREKVRAK(Ac)-I-Aib-IEGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 87

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFSRRAK(Ac)-NH ₂

SEQ ID NO: 88

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Hly-RAK(Ac)-NH ₂

SEQ ID NO: 89

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-ST-Mph-SRRAK(Ac)-NH ₂

SEQ ID NO: 90

Ac-LEGREKVRAK(Ac)-IA-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 91

Ac-LEGRERVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-ST-Pfp-S-Aib-RRK(Ac)-NH ₂

SEQ ID NO: 92

Ac-LEGRERVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-ST-Trp(5-F)-S-Aib-RRK(Ac)-NH ₂

SEQ ID NO: 93

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFTRRAK(Ac)-NH ₂

SEQ ID NO: 94

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Palm)-STFVRRAK(Ac)-NH ₂

SEQ ID NO: 95

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Myr)-STFS-Mly-RAK(Ac)-NH ₂

SEQ ID NO: 96

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-Myr)-STFS-Mly-RAK-NH ₂

SEQ ID NO: 97

Ac-LEGREKVRAK(Ac)-I-Aib-Aib-EGK(TTDS-TTDS-TTDS-gE-gE-gE-gE-Myr)-STFS-Mly-RAK-NH ₂

SEQ ID NO: 100=relaxin H2 chain A

H -Gln-Leu-Tyr-Ser-Ala-Leu-Ala-Asn-Lys-Cys-Cys-His-Val-Gly-Cys-Thr-Lys-Arg-Ser-Leu-Ala-Arg-Phe-Cys- OH

SEQ ID NO: 101=relaxin H2 chain B

H -Asp-Ser-Trp-Met-Glu-Glu-Val-Ile-Lys-Leu-Cys-Gly-Arg-Glu-Leu-Val-Arg-Ala-Gln-Ile-Ala-Ile-Cys-Gly- Met-Ser-Thr-Trp-Ser-OH

SEQ ID NO: 102=SEQ ID B7-33 C11,23S*

H -Val-Ile-Lys-Leu-Ser-Gly-Arg-Glu-Leu-Val-Arg-Ala-Gln-Ile-Ala-Ile-Ser-Gly-Met-Ser-Thr-Trp-Ser-Lys- Arg-Ser-Leu-NH ₂

SEQ ID NO: 103=SEQ ID AcB7-33 C11,23S*

Ac-Val-Ile-Lys-Leu-Ser-Gly-Arg-Glu-Leu-Val-Arg-Ala-Gln-Ile-Ala-Ile-Ser-Gly-Met-Ser-Thr-Trp-Ser-Lys- Arg-Ser-Leu-NH ₂

SEQ ID NO: 104=SEQ ID KKKK(AcB7-29 C11,23S)*

Ac-Val-Ile-Lys-Leu-Ser-Gly-Arg-Glu-Leu-Val-Arg-Ala-Gln-Ile-Ala-Ile-Ser-Gly-Met-Ser-Thr-Trp-Ser-Lys- Lys-Lys-Lys-NH ₂

*comparative examples

--->

LIST OF SEQUENCES

<110> SANOFI

<120> MODIFIED LIPIDATED RELAXIN B-CHAIN PEPTIDES AND THEIR

THERAPEUTIC USE

<130>PR82713/KLP/MGG/gg

<150>EP18305094

<151> 2018-01-31

<160> 104

<170> BiSSAP 1.3.6

<210> 1

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 1

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 2

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 2

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 3

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 3

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 4

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)2-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)2-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 4

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 5

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2)4-(gamma-glutamic acid)-3-palmitoyl group

(-(PEG2)4-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 5

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 6

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)2-(gamma-glutamic acid)-3-stearoyl group

(-(TTDS)2-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 6

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 7

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-stearoyl group

(-(TTDS)3-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 7

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 8

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2)4-(gamma-glutamic acid)-3-palmitoyl group

(-(PEG2)4-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 8

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 9

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)2-(gamma-glutamic acid)-2-palmitoyl group

(-(TTDS)2-(gE)2-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 9

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 10

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)2-(gamma-glutamic acid)-4-palmitoyl group

(-(TTDS)2-(gE)4-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 10

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 11

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 11

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Ala Xaa

20

<210> 12

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 is citrulline (Cit)

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 12

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 13

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 13

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Lys Arg Ala Xaa

20

<210> 14

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 20

<223> Xaa at position 20 is D-serine (Dser)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 14

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Xaa Lys Arg Ala Xaa

20

<210> 15

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 20

<223> Xaa at position 20 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 15

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Xaa Lys Arg Ala Xaa

20

<210> 16

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)2-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)2-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is D-lysine (Dlys)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 16

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 17

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)2-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)2-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is D-lysine (Dlys)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 17

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Ala Xaa

20

<210> 18

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)2-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)2-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is D-lysine (Dlys)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 18

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 19

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2)3-(gamma-glutamic acid)-3-palmitoyl group

(-(PEG2)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 19

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 20

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-stearoyl group

(-(TTDS)3-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 20

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 21

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2)4-(gamma-glutamic acid)-3-stearoyl group

(-(PEG2)4-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 21

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 22

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2DGA)3-(gamma-glutamic acid)-3-palmitoyl group

(-(PEG2DGA)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 22

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 23

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 23

Leu Glu Gly Arg Glu Leu Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 24

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 24

Leu Glu Gly Arg Glu Phe Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 25

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 25

Leu Glu Gly Arg Glu Gln Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 26

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2)4-(gamma-glutamic acid)-3-stearoyl group

(-(PEG2)4-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 26

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 27

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 27

Leu Glu Gly Arg Glu Arg Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 28

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 6

<223> Xaa at position 6 is a homolysin (Hly)

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 28

Leu Glu Gly Arg Glu Xaa Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 29

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 9

<223> Xaa at position 9 is 2-aminoisobutyric acid

(Aib)

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 29

Leu Glu Gly Arg Glu Lys Val Arg Xaa Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 30

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-stearoyl group

(-(TTDS)3-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 30

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Ala Xaa

20

<210> 31

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 31

Leu Glu Gly Arg Glu Arg Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Arg Xaa

20

<210> 32

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2DGA)3-(gamma-glutamic acid)-3-stearoyl group

(-(PEG2DGA)3-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 32

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 33

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)2-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)2-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 33

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 34

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)2-(gamma-glutamic acid)-3-stearoyl group

(-(TTDS)2-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 34

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 35

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 20

<223> Xaa at position 20 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 35

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Xaa Lys Arg Ala Xaa

20

<210> 36

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is D-lysine (Dlys)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 36

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 37

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 37

Leu Glu Gly Arg Glu Leu Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Arg Xaa

20

<210> 38

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2)3-(gamma-glutamic acid)-3-palmitoyl group

(-(PEG2)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 38

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 39

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 39

Leu Glu Gly Arg Glu Phe Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Arg Xaa

20

<210> 40

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 40

Leu Glu Gly Arg Glu Gln Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Arg Xaa

20

<210> 41

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2DGA)3-(gamma-glutamic acid)-3-palmitoyl group

(-(PEG2DGA)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 41

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Ala Xaa

20

<210> 42

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2)4-(gamma-glutamic acid)-3-palmitoyl group

(-(PEG2)4-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 42

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Ala Xaa

20

<210> 43

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 6

<223> Xaa at position 6 is a homolysin (Hly)

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-stearoyl group

(-(TTDS)3-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 43

Leu Glu Gly Arg Glu Xaa Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Ala Xaa

20

<210> 44

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 20

<223> Xaa at position 20 is D-serine (Dser)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 44

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Xaa Lys Arg Ala Xaa

20

<210> 45

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2)5-(gamma-glutamic acid)-3-palmitoyl group

(-(PEG2)5-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 45

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 46

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2)5-(gamma-glutamic acid)-4-palmitoyl group

(-(PEG2)5-(gE)4-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 46

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 47

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 47

Leu Glu Gly Arg Glu Lys Val Arg Ala Lys Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 48

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 48

Leu Glu Gly Arg Glu Lys Val Arg Ala Gln Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 49

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl group

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 49

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Lys

20

<210> 50

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2DGA)3-(gamma-glutamic acid)-3-stearoyl group

(-(PEG2DGA)3-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 50

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 51

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-4-stearoyl group

(-(TTDS)3-(gE)4-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 51

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 52

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-2-stearoyl group

(-(TTDS)3-(gE)2-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 52

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 53

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(PEG2DGA)3-(gamma-glutamic acid)-4-stearoyl group

(-(PEG2DGA)3-(gE)4-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 53

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 54

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)2-(gamma-glutamic acid)-4-stearoyl group

(-(TTDS)2-(gE)4-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 54

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 55

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 55

Leu Glu Gly Arg Glu Arg Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Arg Xaa

20

<210> 56

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 is citrulline (Cit)

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-stearoyl

(-(TTDS)3-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 56

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 57

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is homolysin (Hly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 57

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Ala Xaa

20

<210> 58

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)4-(gamma-glutamic acid)-3-stearoyl

(-(TTDS)3-(gE)4-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 58

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Ala Xaa

20

<210> 59

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)4-(gamma-glutamic acid)-3-stearoyl

(-(TTDS)3-(gE)4-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 59

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Lys Xaa

20

<210> 60

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)2-(gamma-glutamic acid)-3-stearoyl

(-(TTDS)3-(gE)2-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 60

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Lys Xaa

20

<210> 61

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-stearoyl

(-(TTDS)3-(gE)3-Stea)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 61

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Lys Xaa

20

<210> 62

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-4-palmitoyl

(-(TTDS)3-(gE)4-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 62

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 63

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 63

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Gln Trp Ser Xaa Arg Lys Xaa

20

<210> 64

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 64

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Arg Trp Ser Xaa Arg Lys Xaa

20

<210> 65

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 9

<223> Xaa at position 9 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 65

Leu Glu Gly Arg Glu Lys Val Arg Xaa Gln Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 66

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 20

<223> Xaa at position 20 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 66

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Xaa Xaa Arg Ala Xaa

20

<210> 67

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 67

Leu Glu Gly Arg Glu Arg Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 68

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 23

<223> Xaa at position 23 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 68

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Xaa Lys

20

<210> 69

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 23

<223> Xaa at position 23 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 69

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Xaa Arg

20

<210> 70

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 70

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Ile Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 71

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 71

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Ala Lys

20

<210> 72

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 20

<223> Xaa at position 20 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 72

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Xaa Arg Arg Ala Xaa

20

<210> 73

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 73

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Lys Trp Ser Xaa Arg Ala Lys

20

<210> 74

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)4-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)4-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 74

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Ile Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Lys Xaa

20

<210> 75

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)4-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)4-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 75

Leu Glu Gly Arg Glu Arg Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Arg Xaa

20

<210> 76

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 76

Leu Glu Gly Arg Glu Arg Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Arg Xaa

20

<210> 77

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)4-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)4-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 77

Leu Glu Gly Arg Glu Arg Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Arg Xaa

20

<210> 78

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)4-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)4-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 78

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 79

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 79

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Lys Phe Ser Xaa Arg Lys Xaa

20

<210> 80

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 19

<223> Xaa at position 19 is 5-chlorotryptophan

(Trp(5Cl))

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 80

Leu Glu Gly Arg Glu Arg Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Xaa Ser Xaa Arg Arg Xaa

20

<210> 81

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 1

<223> Xaa at position 1 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 81

Xaa Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 82

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 9

<223> Xaa at position 9 is 2-aminoisobutyric acid

(Aib)

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 82

Leu Glu Gly Arg Glu Lys Val Arg Xaa Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Ala Xaa

20

<210> 83

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 83

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Lys Trp Ser Xaa Arg Lys Xaa

20

<210> 84

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 84

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Ile Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 85

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 9

<223> Xaa at position 9 is 2-aminoisobutyric acid

(Aib)

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 85

Leu Glu Gly Arg Glu Arg Val Arg Xaa Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Trp Ser Xaa Arg Arg Xaa

20

<210> 86

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 1

<223> Xaa at position 1 is 2-aminoisobutyric acid

(Aib)

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 86

Xaa Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Ile Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 87

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 87

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Arg Arg Ala Xaa

20

<210> 88

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is homolysin (Hly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 88

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 89

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 19

<223> Xaa at position 19 is α-methylphenylalanine (Mph)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 89

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Xaa Ser Arg Arg Ala Xaa

20

<210> 90

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 90

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Ala Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 91

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 19

<223> Xaa at position 19 is 4-fluorophenylalanine (Pfp)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 91

Leu Glu Gly Arg Glu Arg Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Xaa Ser Xaa Arg Arg Xaa

20

<210> 92

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 19

<223> Xaa at position 19 is 5-fluorotryptophan (Trp(5F))

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 92

Leu Glu Gly Arg Glu Arg Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Xaa Ser Xaa Arg Arg Xaa

20

<210> 93

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 93

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Thr Arg Arg Ala Xaa

20

<210> 94

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)-3-palmitoyl

(-(TTDS)3-(gE)3-Palm)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 94

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Val Arg Arg Ala Xaa

20

<210> 95

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)3-myristoyl

(-(TTDS)3-(gE)3-Myr)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<220>

<221> OPTION

<222> 24

<223> Xaa at position 24 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<400> 95

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Xaa

20

<210> 96

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)3-myristoyl

(-(TTDS)3-(gE)3-Myr)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 96

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Lys

20

<210> 97

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 10

<223> Xaa at position 10 represents

2-amino-4-acetamidohexanoic acid-Nε-acetyl-lysine-K(Ac))

<220>

<221> OPTION

<222> 12

<223> Xaa at position 12 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 13

<223> Xaa at position 13 is a 2-aminoisobutyric

acid (Aib)

<220>

<221> OPTION

<222> 16

<223> Xaa at position 16 is the amino acid lysine,

bonded at the nitrogen atom of its side chain to

-(TTDS)3-(gamma-glutamic acid)4-myristoyl

(-(TTDS)3-(gE)4-Myr)

<220>

<221> OPTION

<222> 21

<223> Xaa at position 21 is α-methyllysine (Mly)

<220>

<221> OPTION

<222> 24

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 97

Leu Glu Gly Arg Glu Lys Val Arg Ala Xaa Ile Xaa Xaa Glu Gly Xaa

1 5 10 15

Ser Thr Phe Ser Xaa Arg Ala Lys

20

<210> 98

<400> 98

000

<210> 99

<400> 99

000

<210> 100

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Chain A of relaxin H2

<220>

<223> Chain A of relaxin H2

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by a hydrogen atom (H) in its N-terminal region

<400> 100

Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr

1 5 10 15

Lys Arg Ser Leu Ala Arg Phe Cys

20

<210> 101

<211> 29

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin H2 chain B

<220>

<223> Relaxin H2 chain B

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by a hydrogen atom (H) in its N-terminal region

<400> 101

Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val

1 5 10 15

Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser

20 25

<210> 102

<211> 27

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue - comparative example

<220>

<223> Relaxin-2 B-chain peptide analogue - comparative example

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by a hydrogen atom (H) in its N-terminal region

<220>

<221> OPTION

<222> 27

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 102

Val Ile Lys Leu Ser Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile

1 5 10 15

Ser Gly Met Ser Thr Trp Ser Lys Arg Ser Leu

20 25

<210> 103

<211> 27

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue - comparative example

<220>

<223> Relaxin-2 B-chain peptide analogue - comparative example

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 27

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 103

Val Ile Lys Leu Ser Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile

1 5 10 15

Ser Gly Met Ser Thr Trp Ser Lys Arg Ser Leu

20 25

<210> 104

<211> 27

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Relaxin-2 B-chain peptide analogue - comparative example

<220>

<223> Relaxin-2 B-chain peptide analogue - comparative example

<220>

<221> OPTION

<222> 1

<223> The peptide is replaced by an acetyl (Ac) group in its N-terminal

region

<220>

<221> OPTION

<222> 27

<223> The peptide is replaced by a -NH2 group in its C-terminal region

<400> 104

Val Ile Lys Leu Ser Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile

1 5 10 15

Ser Gly Met Ser Thr Trp Ser Lys Lys Lys Lys

20 25

<---

Claims (84)

1. A peptide capable of activating the RXFP1 receptor, wherein the peptide is characterized by the following formula (I) in the Nter _{- Cter} direction: Ac-X ₁₀ -EGREX ₁₅ -VRX ₁₈ -X ₁₉ -IX ₂₁ -X ₂₂ -EGX 25 -SX ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -X ₃₁ -X _{32 -X 33} -NH ₂ , where N _ter represents the N-terminal region of the peptide; C _ter represents the C-terminal region of the peptide; Ac represents an acetyl group; X ₁₀ is an amino acid selected from the group consisting of leucine, 2-aminoisobutyric acid, Nε-acetyllysine and α-methylleucine; X ₁₅ is an amino acid selected from the group consisting of lysine, arginine, homolysine, homoarginine, ornithine, glutamine, phenylalanine and leucine; X ₁₈ is an amino acid selected from the group consisting of alanine, 2-aminoisobutyric acid, leucine, Nε-acetyllysine and glutamine; X ₁₉ is an amino acid selected from the group consisting of lysine, Nε-acetyl-lysine, citrulline, glutamine, alanine and 2-aminoisobutyric acid; I is isoleucine; X ₂₁ is an amino acid selected from the group consisting of 2-aminoisobutyric acid and alanine; X ₂₂ is an amino acid selected from the group consisting of 2-aminoisobutyric acid and isoleucine; X ₂₅ has the following structure: , wherein * represents a covalent bond with glycine preceding X ₂₅ in formula (I); represents a covalent bond with the serine following X ₂₅ in formula (I); And Z represents a group of formula (II) -[(PEGxx) _b (gE) _c C _d ], b and c are independently equal to 1, 2, 3, 4 or 5; PEGxx is independently a polyethylene glycol derivative selected from the group consisting of PEG ₂ , PEG ₂ DGA and TTDS; gE is gamma-glutamic acid; And _Cd represents a linear saturated C ₁₂ -C ₂₂ acyl group; X ₂₇ is an amino acid selected from the group consisting of threonine, lysine, arginine and glutamine; X ₂₈ is an amino acid selected from the group consisting of tryptophan, phenylalanine, 5-fluorotryptophan, 5-chlorotryptophan, 5-methoxytryptophan, tyrosine, 4-fluorophenylalanine, 1-naphthylalanine, 2-naphthylalanine, α-methyltryptophan, α-methylphenylalanine and 5-hydroxytryptophan; X ₂₉ is an amino acid selected from the group consisting of serine, D-serine, 2-aminoisobutyric acid, threonine, α-methylserine, Nε-acetyllysine and valine; X ₃₀ is an amino acid selected from the group consisting of 2-aminoisobutyric acid, α-methyllysine, D-lysine, lysine, homolysine, ornithine, arginine and α-methylarginine; X ₃₁ is an amino acid selected from the group consisting of arginine, Nω-methylarginine, alanine, Nω,Nω'-dimethylarginine and citrulline; X ₃₂ is an amino acid selected from the group consisting of lysine, alanine, arginine, Nε-acetyllysine and Nε,Nε,Nε-trimethyllysine; And X ₃₃ is an amino acid selected from lysine, Nε-acetyllysine, leucine, arginine and alanine; or a salt or solvate thereof. 2. The peptide according to claim 1, where b is equal to 2, 3, 4 or 5, and c is equal to 2, 3 or 4; or a salt or solvate thereof. 3. The peptide according to claim 1 or 2, where C _d represents a linear saturated acyl group selected from the group consisting of acyl groups C ₁₂ (Lau), C ₁₄ (Myr), C ₁₅ (Penta), C ₁₆ (Palm ), C ₁₇ (Hepta), C ₁₈ (Stea), C ₂₀ (Eico) and C ₂₂ (Doco), in particular a linear saturated acyl group selected from the group consisting of C ₁₂ (Lau), C ₁₄ ( Myr), C ₁₅ (Penta), C ₁₆ (Palm), C ₁₇ (Hepta) or C ₁₈ (Stea), and in particular a linear C ₁₆ or C ₁₈ acyl group; or a salt or solvate thereof. 4. Peptide according to any one of paragraphs. 1-3, characterized by the following formula (Ib) in the Nter-Cter direction: Ac-X ₁₀ -EGREX ₁₅ -VRX ₁₈ -X ₁₉ -IX ₂₁ -X ₂₂ -EGX ₂₅ -SX ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -RX ₃₂ -X ₃₃ -NH ₂ , where N _ter represents the N-terminal region of the peptide; C _ter represents the C-terminal region of the peptide; Ac represents an acetyl group; X ₁₀ is an amino acid selected from the group consisting of leucine, Nε-acetyllysine and 2-aminoisobutyric acid; X ₁₅ is an amino acid selected from the group consisting of lysine, arginine, homolysine, glutamine, phenylalanine and leucine; X ₁₈ is an amino acid selected from the group consisting of alanine, 2-aminoisobutyric acid and Nε-acetyllysine; X ₁₉ is an amino acid selected from the group consisting of lysine, Nε-acetyllysine, glutamine and citrulline; X ₂₁ is an amino acid selected from the group consisting of 2-aminoisobutyric acid and alanine; X ₂₂ is an amino acid selected from the group consisting of 2-aminoisobutyric acid and isoleucine; X ₂₅ has the following structure: , wherein * represents a covalent bond with glycine preceding X ₂₅ in formula (Ia); represents a covalent bond with the serine following X ₂₅ in formula (Ia); And Z is selected from the group consisting of -(TTDS) ₂ -(gE) ₃ -Palm, -(TTDS) ₃ -(gE) ₃ -Palm, -(PEG ₂ DGA) ₃ -(gE) ₃ -Palm, -( PEG ₂ ) ₄ -(gE) ₃ -Palm, -(TTDS) ₂ -(gE) ₂ -Palm, -(TTDS) ₂ -(gE) ₃ -Stea, -(TTDS) ₃ -(gE) ₃ -Stea , -(PEG ₂ DGA) ₃ -(gE) ₃ -Stea, -(PEG ₂ DGA) ₃ -(gE) ₄ -Stea, -(PEG ₂ ) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE) ₃ -Stea, -(PEG ₂ ) ₅ -(gE) ₃ -Palm, -(PEG ₂ ) ₅ -(gE) ₄ -Palm, -(TTDS) ₃ -(gE) ₄ -Stea, -(TTDS) ₂ -(gE) ₄ -Palm, -(TTDS) ₃ -(gE) ₂ -Stea, -(TTDS) ₂ -(gE) ₄ -Stea, -(TTDS) ₄ -(gE) ₃ - Stea, -(TTDS) ₃ -(gE) ₄ -Palm, -(TTDS) ₄ -(gE) ₃ -Palm, -(TTDS) ₃ -(gE) ₃ -Myr and -(TTDS) ₃ -(gE) ₄ -Myr, where gE represents gamma-glutamic acid; Palm is palmitoyl and Stea is stearoyl; X ₂₇ is an amino acid selected from the group consisting of threonine, glutamine, arginine and lysine; X ₂₈ is an amino acid selected from the group consisting of tryptophan, phenylalanine, 5-chlorotryptophan, α-methylphenylalanine, 4-fluorophenylalanine and 5-fluorotryptophan; X ₂₉ is an amino acid selected from the group consisting of serine, D-serine, 2-aminoisobutyric acid, Nε-acetyllysine, threonine and valine; X ₃₀ is an amino acid selected from the group consisting of 2-aminoisobutyric acid, α-methyllysine, D-lysine, lysine, homolysine and arginine; X ₃₂ is an amino acid selected from the group consisting of lysine, alanine, arginine and Nε-acetyllysine; And X ₃₃ is an amino acid selected from lysine, Nε-acetyllysine and arginine; or a salt or solvate thereof. 5. Peptide according to any one of paragraphs. 1-4, having an amino acid sequence selected from the group consisting of the amino acid sequences under reference SEQ ID NO: 1-97. 6. Peptide according to any one of paragraphs. 1-5, characterized by formula (Ib), where Z is selected from the group consisting of -(TTDS) ₂ -(gE) ₃ -Palm, -(TTDS) ₃ -(gE) ₃ -Palm, -(PEG ₂ DGA) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE) ₃ -Palm, -(TTDS) ₂ -(gE) ₂ -Palm, -(TTDS) ₂ -(gE) ₃ -Stea, - (TTDS) ₃ -(gE) ₃ -Stea, -(PEG ₂ DGA) ₃ -(gE) ₃ -Stea, -(PEG ₂ ) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE ) ₃ -Stea, -(PEG ₂ ) ₅ -(gE) ₃ -Palm, -(TTDS) ₃ -(gE) ₄ -Stea, -(TTDS) ₂ -(gE) ₄ -Palm, -(TTDS) ₂ -(gE) ₄ -Stea, -(TTDS) ₄ -(gE) ₃ -Stea, -(TTDS) ₃ -(gE) ₄ -Palm, -(TTDS) ₄ -(gE) ₃ -Palm, -(TTDS ) ₃ -(gE) ₃ -Myr and -(TTDS) ₃ -(gE) ₄ -Myr; or a salt or solvate thereof. 7. Peptide according to any one of paragraphs. 1-6, having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 6, 7, 9-12, 20-22, 26, 28, 30-34, 45, 47-49, 51, 54- 62, 64, 67-69, 71-86, 91, 93 and 96. 8. Peptide according to any one of paragraphs. 1-7, having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 6, 7, 20, 26, 30-34, 45, 48, 49, 51, 54-61, 67, 71, 73, 75-79, 81, 83-92 and 97. 9. Peptide according to any one of paragraphs. 1-8, having an amino acid sequence selected from the group consisting of the amino acid sequences referenced SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 20. 10. Peptide according to any one of paragraphs. 1-9, having the amino acid sequence of reference SEQ ID NO: 3. 11. A pharmaceutical composition for the prevention or treatment of a disease or condition associated with the relaxin receptor RXFP1, containing a therapeutically effective amount of at least one peptide according to any one of paragraphs. 1-10 or a pharmaceutically acceptable salt or solvate thereof together with at least one pharmaceutically acceptable carrier. 12. Use of a peptide according to any one of paragraphs. 1-10, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 11 as a medicinal product in the treatment or prevention of diseases or conditions associated with the RXFP1 receptor. 13. Use of a peptide according to any one of paragraphs. 1-10, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 11 for the treatment or prevention of various diseases or conditions associated with the RXFP1 receptor. 14. Use according to claim 12 or 13, where the diseases or conditions are selected from the group consisting of fibrosis; fibrotic diseases, in particular systemic sclerosis, scleroderma and fibromyalgia; idiopathic pulmonary fibrosis; kidney diseases associated with fibrosis; pulmonary hypertension and preeclampsia. 15. Use according to claim 12 or 13, where the diseases or conditions are selected from the group consisting of diseases of the heart and blood vessels, in particular from the group consisting of acute or chronic heart failure, systolic or diastolic heart failure, coronary heart disease, atherosclerosis, microvascular angina and cardiovascular complications of diabetes. 16. Use according to claim 12 or 13, where the diseases or conditions are selected from the group consisting of types of renal failure, in particular renal dysfunction with cirrhosis; chronic renal failure and acute renal failure. 17. The peptide according to claim 3, where C _d represents a linear saturated acyl group selected from the group consisting of acyl group C ₁₂ (Lau), C ₁₄ (Myr), C ₁₅ (Penta), C ₁₆ (Palm), C ₁₇ (Hepta) or C ₁₈ (Stea); or a salt or solvate thereof. 18. The peptide according to claim 17, where C _d represents a linear acyl group C ₁₆ or C ₁₈ ; or a salt or solvate thereof. 19. The peptide according to claim 4, containing an amino acid sequence selected from the group consisting of amino acid sequences under reference SEQ ID NO: 1-97. 20. The peptide according to claim 1, where Z is selected from the group consisting of -(TTDS) ₂ -(gE) ₃ -Palm, -(TTDS) ₃ -(gE) ₃ -Palm, -(PEG ₂ DGA) ₃ - (gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE) ₃ -Palm, -(TTDS) ₂ -(gE) ₂ -Palm, -(TTDS) ₂ -(gE) ₃ -Stea, -(TTDS ) ₃ -(gE) ₃ -Stea, -(PEG ₂ DGA) ₃ -(gE) ₃ -Stea, -(PEG2) ₃ -(gE) ₃ -Palm, -(PEG ₂ ) ₄ -(gE) ₃ - Stea, -(PEG ₂ ) ₅ -(gE) ₃ -Palm, -(TTDS) ₃ -(gE) ₄ -Stea, -(TTDS) ₂ -(gE) ₄ -Palm, -(TTDS) ₂ -(gE ) ₄ -Stea, -(TTDS) ₄ -(gE) ₃ -Stea, -(TTDS) ₃ -(gE) ₄ -Palm, -(TTDS) ₄ -(gE) ₃ -Palm, -(TTDS) ₃ - (gE) ₃ -Myr and -(TTDS) ₃ -(gE) ₄ -Myr; or a salt or solvate thereof. 21. A pharmaceutical composition for the prevention or treatment of a disease or condition associated with the relaxin receptor RXFP1, containing a therapeutically effective amount of at least one peptide according to claim 5 or a pharmaceutically acceptable salt or solvate thereof together with at least one pharmaceutically acceptable carrier. 22. A method of preventing or treating a disease or condition associated with the relaxin receptor RXFP1, comprising administering to an individual in need of said prevention or treatment the peptide of claim 1 or a pharmaceutically acceptable salt or solvate thereof. 23. The method of claim 22, wherein the disease or condition is selected from the group consisting of fibrosis, fibrotic diseases, idiopathic pulmonary fibrosis, kidney diseases associated with fibrosis, pulmonary hypertension and preeclampsia. 24. The method of claim 23, wherein the disease or condition is a fibrotic disease selected from the group consisting of systemic sclerosis, scleroderma and fibromyalgia. 25. The method of claim 22, wherein the disease or condition is selected from the group consisting of heart disease and vascular disease. 26. The method of claim 25, wherein the disease or condition is selected from the group consisting of acute or chronic heart failure, systolic or diastolic heart failure, coronary artery disease, atherosclerosis, microvascular angina, and a cardiovascular complication of diabetes. 27. The method of claim 22, wherein the disease or condition is renal failure. 28. The method of claim 27, wherein the disease or condition is selected from renal dysfunction in cirrhosis, chronic renal failure and acute renal failure.

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