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WO2020053200A1 - Peptides destinés à être utilisés dans le traitement du psoriasis - Google Patents

Peptides destinés à être utilisés dans le traitement du psoriasis Download PDF

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Publication number
WO2020053200A1
WO2020053200A1 PCT/EP2019/074088 EP2019074088W WO2020053200A1 WO 2020053200 A1 WO2020053200 A1 WO 2020053200A1 EP 2019074088 W EP2019074088 W EP 2019074088W WO 2020053200 A1 WO2020053200 A1 WO 2020053200A1
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WO
WIPO (PCT)
Prior art keywords
seq
peptide
wnt5a
treatment
derivatives
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2019/074088
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English (en)
Inventor
Tommy Andersson
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Wntresearch AB
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Wntresearch AB
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Filing date
Publication date
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Publication of WO2020053200A1 publication Critical patent/WO2020053200A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to Wnt5A peptides, and derivatives thereof for use in the treatment of psoriasis.
  • the present invention also re- lates to compositions for the treatment of psoriasis.
  • this inven- tion relates to a composition for the administration of the Wnt5A peptide sys- temically or topically.
  • Psoriasis is a chronic, noncontagious, autoimmune and multisystem disease, which most commonly manifests itself on the skin by red, raised plaques and papules with silvery and/or whitish scales.
  • NASH Na- tional Institutes of Health
  • approximately 2.2% of the United States population has psoriasis.
  • the incidence varies greatly among populations, from around 0.1 % to 3%, with approximately 2-3% of people being affected worldwide.
  • Psoriatic patients have increased risk of early mortality and may develop comorbidities such as psoriatic arthritis, cardiovascular disease, and diabetes.
  • the disease may cover large areas of skin, including areas such as the hands and face.
  • the disease is associated with anxiety, depression, and social isolation, and can negatively impact patients' personal relationships and professional careers.
  • keratinocyte proliferation is induced by a large number activated T cells that infiltrate the epidermis.
  • a deregulated inflammatory process ensues with a significant pro-duction of cytokines, e.g. tumour necrosis factor-a [TNF-a], interferon- gamma, interleukin-12.
  • treatments for psoriasis include topical therapy, photothera- py, and non-biologic and biologic systemic drugs.
  • infliximab One example treatment utilises infliximab.
  • infliximab is adminis- tered intravenously, and patients generally does not prefer subcutaneous bio- logics.
  • biologic agents present the most efficacious treatment currently available a significant proportion of psoriatic patients do not respond or only partially respond to biological agents, or, over time, expe- rience a loss of responsiveness compared to the initial response.
  • the present invention has been made from a consideration of this.
  • a Wnt5A peptide and derivatives thereof for use in the treatment of psoriasis comprising XADGXBEL (SEQ. ID. NO.
  • XA methionine (M) or norleucine
  • XB cysteine (C) or alanine (A)
  • Wnt5A peptide has a t-butoxycarbonyl protecting group in amino acid position 1 , wherein the amino acid residues of said Wnt5A peptide, ex- cept glycine, are either in the L- or D-stereoisomeric form, and wherein the total length of the peptide is equal to or less than 50 amino acids.
  • Wnt5A peptides and derivatives of the form outlined above can be used in the treatment of psoriasis.
  • the mechanism underlying this is not at present well understood.
  • t-butoxycarbonyl protected Wnt5A peptides act as an antagonist, thereby resulting in blockage of the Wnt5A hoh-b-catenin dependent signalling pathway in the affected cells.
  • the total length of the peptide is equal to or less than 20 amino acids.
  • the Wnt5A peptide or any deriva- tives thereof for use in the treatment of psoriasis comprises the amino acid sequence MDGCEL, wherein the Wnt5A peptide has a t-butoxycarbonyl pro- tecting group in amino acid position 1.
  • At least one Wnt5A peptide and derivatives thereof for use in the treatment of psoriasis is selected from the group con- sisting of:
  • GMDGCEL (SEQ. ID. NO. 4),
  • KTSEGMDGCEL SEQ. ID. NO. 8
  • NKTSEGMDGCEL (SEQ. ID. NO. 9),
  • LGTQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 17),
  • Wnt5A peptide has a t-butoxycarbonyl protecting group in amino acid position 1.
  • the Wnt5A peptide and derivatives thereof for use in the treatment of psoriasis the peptide is hexapeptide MDGCEL, wherein M of the hexapeptide has a t-butoxycarbonyl protecting group (SEQ. ID. NO. 3).
  • SEQ. ID. NO. 3 M of the hexapeptide has a t-butoxycarbonyl protecting group.
  • This particular hexapeptide is also denoted BOX5.
  • the Wnt5A peptide and derivatives thereof for use in the treatment of psoriasis may corn- prise the amino acid sequence MDGAEL, NleDGAEL or NleDGCEL, wherein Nle is norleucine.
  • the Wnt5A peptide according to the invention may be used in the treatment of psoriasis, wherein the psoriasis is vulgaris/plaque, guttate, inverse, pustular, palmoplantar or erythrodermic psoriasis.
  • the Wnt5A peptide according to the invention may be formulated for systemically, locally or topically administration.
  • the pharmaceutically acceptable agent can be administered by various routes, either systemically or topically.
  • suitable administration forms include, for example, oral formulations; par- enteral injections including intravenous, intramuscular, intradermal and sub- cutaneous injections; and mucosal, topical, transdermal, inhalation, nasal or rectal formulations.
  • Particularly suitable formulations are formulations for local delivery such as topical formulations in the form of ointments, gels, creams, pastes, solutions, suspensions, lotions and emulsions.
  • the required dosage of the Wnt5A peptide will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the administration route and the specific compound being em- ployed.
  • the amount of the Wnt5A peptide in the formulation according to the invention can typically range from 100 to 3,200 pg/mL, for example 200, 500, 800, 1 ,600, 1 ,800, 2,000, 2500 or 3,000 pg/mL.
  • the formulation is a topical formulation comprising 800 pg/mL of Wnt5A.
  • the Wnt5A peptide may be administered once to four times a day and until symp- toms disappear.
  • compositions comprising a therapeutically active amount of the Wnt5A peptide or derivatives thereof according to the invention and at least one carrier component.
  • the composition according to the invention comprises a carrier component that comprises one or more pharmaceutically acceptable excipi- ents adapted for systemically administration.
  • carrier components suita- ble for both local and systemic administration may be chosen from the group of vesicular systems such as transfersomes, ethosomes, penetration enhanc- er-containing vesicles (PEVs), or surfactant based systems such as micro- emulsions, or polymeric nanoparticles such as dendrimers.
  • the composition according to the invention comprises a carrier component that comprises one or more pharmaceutically acceptable excipients adapted for topical administration.
  • carrier components for topical administration may be chosen from the group of liposomes, niosomes, solid lipid nanoparti- cles (SLNs), nanostructured lipid carriers (NLCs), lipospheres, nanoemul- sions, polymeric micelles, polymeric nano and microsperes, nanocapsules.
  • the SLNs may be triglycerides, carnauba wax, beeswax, cetyl alcohol, emul- sifying wax, cholesterol, or cholesterol butyrate.
  • NLCs are tailored SLNs (oil loaded SLNs) composed of solid lipid matrix incorporating a liquid lipid such as soya bean oil, oleic acid, corn oil in the presence of an emulsifier. Owing to their highly lipidic and non-flexible nature, SLNs and NLCs are confined to the topical rather than the transdermal treatment of skin diseases.
  • composition according to the invention may be for use in topical administration and may be in form of cream, gel, ointment, paste, lotion, spray, solution, suspension, emulsion and roll-on formulations.
  • composition comprises a Wnt5A peptide or derivatives thereof wherein XA is M and XB is C and, optionally, the peptide is selected from the group consisting of:
  • GMDGCEL (SEQ. ID. NO. 4),
  • TSEGMDGCEL SEQ. ID. NO. 7
  • KTSEGMDGCEL SEQ. ID. NO. 8
  • NKTSEGMDGCEL (SEQ. ID. NO. 9),
  • LGTQGRLCNKTSEGMDGCEL (SEQ. ID. NO. 17).
  • composition comprises a Wnt5A peptide or derivatives thereof wherein
  • XA is M and XB is A, or
  • XA is norleucine and XB is A, or
  • XA is norleucine and XB is C.
  • a pad, patch, strip, or bandage corn- prising a Wnt5A peptide or composition according to the invention is provided.
  • Fig. 1 shows Box5 as a Wnt5a antagonist by inhibiting Wnt5a-mediated Ca 2+ signalling in skin cells.
  • C Preincubation with Box5 (100 pM) overnight inhibits myristoylated alanine- rich C kinase substrate (MARCKS) phosphorylation after 45 min of rWnt5a stimulation (0.2 pg/mL). 1 nM of the PKC activator, phorbol 12-myristate 13- acetate (PMA) was used as a positive indicator for MARCKS phosphorylation.
  • MARCKS myristoylated alanine- rich C kinase substrate
  • Fig. 2 shows examples of the sectioned and stained animal skin samples at 20x magnification.
  • Fig. 3 shows the average of epidermic thickness and Wnt5A staining of skin from vehicle-treated (normal skin) and imiquimod-treated (psoriasis- like skin) mice.
  • Fig. 4 shows the average of epidermic thickness of skin from 4 different mice treated with imiquimod and Box5 (the dotted line indicates the thickness of only imiquimod-treated mice).
  • peptide refers to a compound consisting of two or more amino ac- ids linked in a chain, the carboxyl group of each acid being joined to the ami- no group of the next by a bond of the type -OC-NH-.
  • polypeptide refers to a chain in which there are numerous linked amino acids.
  • hexapeptide refers to a subset of peptides in which there are six amino acids linked in a chain. Other examples include“dipeptides” in which there are two amino acids,“tripeptides” in which there are three amino acids and so forth.
  • the N-terminal or N-terminus is the end of the peptide chain with a free amine (-NH2) group.
  • the C-terminal of C-terminus is the end of the peptide chain with a free car- boxyl (-COOH) group.
  • a t-butoxycarbonyl, or tert-butoxycarbonyl (t-BOC) group is a protecting group having the following structure:
  • An agonist is a species that binds to a receptor and activates the receptor to produce a biological response.
  • an antagonist is a species that blocks or dampens a biological response by blocking downstream Wnt- 5a signalling, such as Ca 2+ and PKC signalling.
  • systemic administration is a route of administration of an active ingredient, i.e. Wnt5A peptide, into the circulatory system so that the entire body is affected. Administration can take place via enteral administration, i.e. absorption of the drug through the gastrointestinal tract, or parenteral admin- istration, i.e. generally injection, infusion, or implantation.
  • topical administration means application to body surfaces such as the skin or mucous membranes in order to treat a disease such as psoriasis.
  • Example 1 Ability of Box5 to reduce the Wnt5a signalling pathway in skin cells.
  • the Box5 peptide was synthesized by Inbiolabs (sev- eral different production batches of the peptides were used). Peptides were purified by reverse-phase high performance liquid chromatography and the purity of each synthesis was >95% (mass spectrometry, Inbiolabs).
  • Box5 The ability of Box5 to modulate Wnt5a-induced Ca 2+ signalling in melanoma cells was analysed. Box5 was shown to selectively inhibit Wnt5a-induced in- tracellular Ca 2+ signalling, but not the intracellular Ca 2+ signalling induced by endothelin-1 (ET-1 ) or carbachol (Fig. 1A), both of which trigger G protein coupled receptor-induced increases in cytosolic Ca 2+ . Accumulated results revealed that there was >70% inhibition of Wnt5a-induced Ca 2+ signalling by Box5, but the peptide had no such effect on the Ca 2+ signal induced by either ET-1 or carbachol (Fig. 1 B).
  • ET-1 endothelin-1
  • Fig. 1A carbachol
  • Box5 significantly and selectively inhibited Wnt5a- induced Ca 2+ and PKC signalling, both of which are necessary for Wnt5a- mediated functional responses.
  • Box5 functions as a selective antago- nist of Wnt5a-induced melanoma cell migration and invasion by inhibiting Wnt5a signalling in skin cells.
  • Example 2 A thicker epidermis and increased Wnt5a is found in animals topically treated with imiquimod, a compound used to induce psoriasislike conditions in animals.
  • C57BL/6 mice were topically treated with vehicle/control or an imiquimod so- lution.
  • the solutions were applied on the shaved and depilated backs of the animals.
  • the animals were treated once daily for 6 days before the experi- ments were terminated on day 7.
  • Samples from vehicle and imiquimod treat- ed skin were fixed and embedded in paraffin. These embedded samples were sectioned (3-4 pm) and stained with Hematoxylin & Eosin (H&E) or with an anti-Wnt5a antibody. The samples were scored blindly.
  • H&E Hematoxylin & Eosin
  • Fig. 2 shows examples of the sectioned and stained animal skin samples at 20x magnification.
  • Fig. 2 (A) shows the epidermis thickness in imiquimod- treated skin, where a thickness of the epidermis is marked with a green line, showing in this sample a thickness of 110.4 pm.
  • Fig. 2 (B) shows Wnt5a staining of imiquimod-treated skin.
  • Fig. 2 (C) shows the epidermis thickness of normal not imiquimod-treated skin where the thickness of the epidermis is marked with a green line, showing in this sample a thickness of 23.77 pm.
  • Fig. 2 (D) shows Wnt5a staining of normal not imiquimod-treated skin.
  • Fig. 3 outlines the accumulated data of epidermic thickness and Wnt5A stain- ing of skin from control not-imiquimod-treated mice and imiquimod-treated mice, respectively.
  • Example 3 Box5 does not increase the thickness of epidermis in psoriasis-like lesions in Imiquimod treated mice.
  • C57BL/6 mice were topically treated with an imiquimod solution daily for six days. The solutions were applied on the shaved and depilated backs of the animals. These lesions were then treated twice a day with Box5 (80 mg/100 mI dissolved in 5% methylcellulose and 2% PEG40) for 5 days. Skin samples from imiquimod-induced and Box5 treated skin were fixed and embedded in paraffin. These embedded samples were sectioned (3-4 pm) and stained with Hematoxylin & Eosin (H&E). The thickness of the epidermis layer was meas- ured at 15 different locations in each skin sample from imiquimod-induced lesions treated with Box5.
  • Box5 80 mg/100 mI dissolved in 5% methylcellulose and 2% PEG40

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
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  • Biochemistry (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des peptides Wnt5A et des dérivés de ceux-ci, destinés à être utilisés dans le traitement du psoriasis. Le peptide Wnt5A selon l'invention comprend XADGXBEL, XA étant de la méthionine (M) ou de la norleucine, XB étant de la cystéine (C) ou de l'alanine (A), et ledit peptide Wnt5A contenant un groupe protecteur t-butoxycarbonyle en position 1 d'acides aminés. Les résidus d'acides aminés dudit peptide Wnt5A sont sous forme stéréoisomère L ou D, et la longueur totale du peptide est inférieure ou égale à 50 acides aminés.
PCT/EP2019/074088 2018-09-10 2019-09-10 Peptides destinés à être utilisés dans le traitement du psoriasis Ceased WO2020053200A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18193376 2018-09-10
EP18193376.3 2018-09-10

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WO2020053200A1 true WO2020053200A1 (fr) 2020-03-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023111695A1 (fr) 2021-12-16 2023-06-22 Ramakrishna Reddy Isanaka Formulation pharmaceutique anti-angiogénique et anti-inflammatoire stable et combinaison pharmaceutique pour le traitement et la prévention du psoriasis

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010019103A1 (fr) * 2008-08-13 2010-02-18 Forskarpatent I Syd Ab Utilisation de dérivés peptidiques wnt5-a pour le traitement du mélanome et du cancer gastrique
WO2011019651A1 (fr) * 2009-08-10 2011-02-17 Epitherix, Llc Composés d’indazole inhibant la voie de signalisation des wnt et utilisations thérapeutiques de ceux-ci thereof
WO2012113779A1 (fr) * 2011-02-21 2012-08-30 Medizinische Universität Wien Moyens et procédés pour traiter une maladie ou un trouble relatif à la lymphangiogenèse ou prévenir la métastase
US20140206623A1 (en) * 2011-07-01 2014-07-24 Wntresearch Ab Treatment of prostate cancer and a method for determining the prognosis for prostate cancer patients

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010019103A1 (fr) * 2008-08-13 2010-02-18 Forskarpatent I Syd Ab Utilisation de dérivés peptidiques wnt5-a pour le traitement du mélanome et du cancer gastrique
WO2011019651A1 (fr) * 2009-08-10 2011-02-17 Epitherix, Llc Composés d’indazole inhibant la voie de signalisation des wnt et utilisations thérapeutiques de ceux-ci thereof
WO2012113779A1 (fr) * 2011-02-21 2012-08-30 Medizinische Universität Wien Moyens et procédés pour traiter une maladie ou un trouble relatif à la lymphangiogenèse ou prévenir la métastase
US20140206623A1 (en) * 2011-07-01 2014-07-24 Wntresearch Ab Treatment of prostate cancer and a method for determining the prognosis for prostate cancer patients

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DEJMEK JSAFHOLM AKAMP NIELSEN CANDERSSON TLEANDERSSON K: "Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1 alpha signaling in human mammary epithelial cells", MOL CELL BIOL, vol. 26, 2006, pages 6024 - 6036
ROMANOWSKA MEVANS AKELLOCK DBRAY SEMCLEAN KDONANDT SFOERSTER J: "Wnt5a exhibits layer-specific expression in adult skin, is upregulated in psoriasis, and synergizes with type 1 interferon", PLOS ONE, vol. 4, no. 4, 2009, pages e5354
SAFHOLM ALEANDERSSON KDEJMEK JNIELSEN CKVILLOUTREIX BOANDERSSON T: "A formylated hexapeptide ligand mimics the ability of Wnt-5a to impair migration of human breast epithelial cells", J BIOL CHEM, vol. 281, 2006, pages 2740 - 2749, XP002629901, doi:10.1074/JBC.M508386200
YANFEI ZHANG ET AL: "Wnt/[beta]-Catenin and Wnt5a/Ca<sup>2+</sup> Pathways Regulate Proliferation and Apoptosis of Keratinocytes in Psoriasis Lesions", CELLULAR PHYSIOLOGY AND BIOCHEMISTRY., vol. 36, no. 5, 1 January 2015 (2015-01-01), CH, pages 1890 - 1902, XP055542921, ISSN: 1015-8987, DOI: 10.1159/000430158 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023111695A1 (fr) 2021-12-16 2023-06-22 Ramakrishna Reddy Isanaka Formulation pharmaceutique anti-angiogénique et anti-inflammatoire stable et combinaison pharmaceutique pour le traitement et la prévention du psoriasis

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