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WO2025043696A1 - Analogue de polypeptide antiviral - Google Patents

Analogue de polypeptide antiviral Download PDF

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Publication number
WO2025043696A1
WO2025043696A1 PCT/CN2023/116435 CN2023116435W WO2025043696A1 WO 2025043696 A1 WO2025043696 A1 WO 2025043696A1 CN 2023116435 W CN2023116435 W CN 2023116435W WO 2025043696 A1 WO2025043696 A1 WO 2025043696A1
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WO
WIPO (PCT)
Prior art keywords
glu
myristoyl
polypeptide
37arg
aeea
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.)
Pending
Application number
PCT/CN2023/116435
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English (en)
Chinese (zh)
Inventor
冯军
东圆珍
徐宏江
朱洪祥
葛兴枫
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Duomirui Biotechnology Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Original Assignee
Shanghai Duomirui Biotechnology Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Publication date
Application filed by Shanghai Duomirui Biotechnology Co Ltd, Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Shanghai Duomirui Biotechnology Co Ltd
Priority to PCT/CN2023/116435 priority Critical patent/WO2025043696A1/fr
Publication of WO2025043696A1 publication Critical patent/WO2025043696A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C07K14/01—DNA viruses
    • C07K14/02—Hepadnaviridae, e.g. hepatitis B virus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/67—General methods for enhancing the expression

Definitions

  • the present invention belongs to the field of biotechnology, and in particular to the field of long-acting biological drug development, and specifically to an antiviral peptide analog.
  • hepatitis B virus infection is a major global public health issue, with approximately 240 million people infected worldwide. Cirrhosis and liver cancer caused by hepatitis B virus (HBV) also have high morbidity and mortality.
  • Antiviral drugs approved for the treatment of hepatitis B include pegylated interferon ⁇ and 6 nucleoside analogs. The former works by inducing adjacent cells to produce antiviral proteins, while the latter blocks viral replication by inhibiting the activity of HBV-DNA polymerase.
  • pegylated interferon ⁇ has side effects such as flu-like symptoms and abnormal blood routine, and nucleoside analogs have disadvantages such as drug resistance and a large number of inappropriate populations. Therefore, anti-hepatitis B virus therapeutic drugs with new mechanisms of action are urgently needed in clinical practice.
  • Myrcludex B was licensed by MYR GmbH from Vision7 and developed by the University of Heidelberg and Hepatera. Myrcludex B is derived from positions 2-48 of the HBV-L protein and consists of 47 natural amino acid residues and an N-terminal myristoyl group. It is a viral entry inhibitor targeting the sodium-taurocholate co-transporting polypeptide (NTCP).
  • NTCP sodium-taurocholate co-transporting polypeptide
  • Myrcludex B was launched in Europe as a drug for the treatment of hepatitis D.
  • the low-dose intermittent administration method with one injection per day, has caused great pain to patients. If the half-life of Myrcludex B can be extended, the clinical compliance of patients can be greatly improved.
  • the present disclosure provides polypeptide analogs, and also provides pharmaceutical compositions comprising the polypeptide analogs, preparation methods and uses thereof.
  • the present disclosure provides a polypeptide analogue, the general structural formula of which is C 14 -P 1 -U 1 ;
  • GTNLSVPNPLGFFPDHQLDPAFGANSNNPDWDFNPNX1DHWPEANX2VG SEQ ID NO: 1
  • X1 is selected from D-Ala, ⁇ -Ala, GABA, Aib, Abu, Arg, Asp, Asn, Cys, Glu, D-Glu, ⁇ -Glu, Gln, Gly, His, Ile, Leu, Pro, Phe, Ser, Tyr, Thr, Trp, Val or Met
  • X2 is Lys, and an acylation-modified modifying group is present at the ⁇ -amino group thereof
  • C14 is a myristoyl group at the N-terminus of P1
  • U1 is a PAS sequence connected to the C-terminus of P1 , and the PAS sequence consists of Pro, Ala and/or Ser and has 0-300 amino acid residues.
  • C14 is a myristoyl group
  • X1 is selected from D-Ala, ⁇ -Ala, GABA, Aib, Abu, Arg, Asp, Asn, Cys, Glu, D-Glu, ⁇ -Glu, Gln, Gly, His, Ile, Leu, Pro, Phe, Ser, Tyr, Thr, Trp, Val or Met
  • T1 is the modifying group of the acylation modification
  • U1 is a PAS sequence connected to the C-terminus of P1 , wherein the PAS sequence consists of Pro, Ala and/or Ser and has 0-300 amino acid residues.
  • the X 1 is selected from ⁇ -Ala, GABA, Aib, Abu, Arg or Cys, preferably Arg.
  • the acylation-modified modifying group comprises a fatty acid, which can non-covalently bind to albumin to extend the half-life of the polypeptide analog.
  • p is 6-20, 10-20, 14-20, 14-18, or 16-18. In some embodiments, p is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is 16. In some embodiments, p is 18. In some embodiments, p is 20.
  • n is 0, 1, 2, or 3. In some embodiments, n is 0. In other embodiments, n is 1.
  • the Xaa is selected from D-Ala, ⁇ -Ala, GABA, Aib, Abu, Arg, Asp, Asn, Cys, D-Glu, ⁇ -Glu, Gln, Gly, His, Ile, Leu, Lys, Pro, Phe, Ser, Tyr, Thr, Trp, Val or Met.
  • the Xaa is selected from GABA, Aib, D-Ala, ⁇ -Ala, Asp, Cys, ⁇ -Glu, Gly, Pro or Phe.
  • the Xaa is ⁇ -Glu.
  • the Xaa is Pro.
  • the general formula of the modification group of X 2 is: -CO-(CH 2 ) p -R 1 , and its structural formula is:
  • the wavy line represents the connection position of the modifying group to the ⁇ -amino group of X2 .
  • p is 6-20, 10-20, 14-20, 14-18, or 16-18. In some embodiments, p is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is 16. In some embodiments, p is 18. In some embodiments, p is 20.
  • the R 1 is -CH 3 or -COOH.
  • the wavy line represents the connection position of the modifying group to the ⁇ -amino group of X2 .
  • the wavy line represents the connection position of the modifying group to the ⁇ -amino group of X2 .
  • the Xaa is selected from D-Ala, ⁇ -Ala, GABA, Aib, Abu, Arg, Asp, Asn, Cys, D-Glu, ⁇ -Glu, Gln, Gly, His, Ile, Leu, Lys, Pro, Phe, Ser, Tyr, Thr, Trp, Val or Met.
  • the Xaa is selected from GABA, Aib, D-Ala, ⁇ -Ala, Asp, Cys, ⁇ -Glu, Gly, Pro or Phe.
  • the Xaa is ⁇ -Glu.
  • the Xaa is Pro.
  • the R 1 is -CH 3 or -COOH.
  • the PAS sequence has 10-300, 30-300, 50-300 or 30-100 amino acid residues. In some embodiments, the PAS sequence has 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300 amino acid residues. In some embodiments, the PAS sequence has 30, 50, 70, 100, 150, 200 or 300 amino acid residues. In some embodiments, the PAS sequence has 30 amino acid residues. In some embodiments, the PAS sequence has 50 amino acid residues. In some embodiments, the PAS sequence has 100 amino acid residues.
  • Pro accounts for 4% and above, 5% and above, 6% and above or 8% and above of the total number of amino acid residues, preferably 10% and above or 15% and above, more preferably 20% and above. In some embodiments, in the PAS sequence, Pro accounts for 40% and below or 35% and below of the total number of amino acid residues, preferably 30% and below. In some embodiments, in the PAS sequence, Pro accounts for 4%-40%, 10%-40%, 15%-40%, 15%-35%, 20%-35% or 20%-30% of the total number of amino acid residues.
  • Pro accounts for about 4%, about 10%, about 15%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35% or about 40% of the total number of amino acid residues.
  • amino acid sequences of exemplary PAS sequences of the present disclosure are provided in Table S1 below.
  • the PAS sequence has 0 amino acid residues, i.e., the PAS sequence is deleted.
  • the C-terminus of the P 1 is in the form of a carboxyl group (i.e., the C-terminus has a -COOH group) or in the form of an amide formed after amidation of a free carboxyl group (i.e., the C-terminus has a -CONH 2 group).
  • polypeptide analog is selected from the following structural formula:
  • C 14 is myristoyl
  • p is 6-20, 10-20, 14-20, 14-18 or 16-18
  • m is 0, 1, 2, 3, 4 or 5
  • n is 0, 1, 2 or 3
  • R 1 is -CH 3 or -COOH
  • Xaa is selected from D-Ala, ⁇ -Ala, GABA, Aib, Abu, Arg, Asp, Asn, Cys, D-Glu, ⁇ -Glu, Gln, Gly, His, Ile, Leu, Lys, Pro, Phe, Ser, Tyr, Thr, Trp, Val or Met.
  • p is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is 16. In some embodiments, p is 18. In some embodiments, p is 20.
  • n is 0, 1, 2 or 3. In some embodiments, m is 0. In other embodiments, m is 2.
  • n is 0, 1, 2, or 3. In some embodiments, n is 0. In other embodiments, n is 1.
  • C 14 is myristoyl
  • p is 6-20, 10-20, 14-20, 14-18 or 16-18
  • R 1 is -CH 3 or -COOH.
  • p is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • p is 16.
  • p is 18.
  • p is 20.
  • polypeptide analog is selected from the following structural formula:
  • C 14 is myristoyl
  • p is 6-20, 10-20, 14-20, 14-18 or 16-18
  • R 1 is -CH 3 or -COOH
  • Xaa is selected from D-Ala, ⁇ -Ala, GABA, Aib, Abu, Arg, Asp, Asn, Cys, D-Glu, ⁇ -Glu, Gln, Gly, His, Ile, Leu, Lys, Pro, Phe, Ser, Tyr, Thr, Trp, Val or Met.
  • p is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is 16. In some embodiments, p is 18. In some embodiments, p is 20.
  • the Xaa is selected from GABA, Aib, D-Ala, ⁇ -Ala, Asp, Cys, ⁇ -Glu, Gly, Pro or Phe.
  • the Xaa is ⁇ -Glu. In other embodiments, the Xaa is Pro.
  • polypeptide analogs disclosed in the present invention have good NTCP binding ability.
  • the Myristoyl-P 1 37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 18 -COOH)-PAS100 (i.e., the polypeptide analogs shown in structural formula 14) have good NTCP binding ability.
  • the polypeptide analogs disclosed herein exhibit a good half-life while maintaining good viral infection inhibitory activity.
  • the polypeptide analogs disclosed herein have good in vivo antiviral activity.
  • the Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 18 -COOH)-PAS100 has good in vivo antiviral activity.
  • the polypeptide analogs disclosed herein have a good half-life in mice.
  • the Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 18 -COOH)-PAS100 has a good half-life in mice.
  • the polypeptide analogs disclosed herein have a good half-life in dogs.
  • the Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 18 -COOH)-PAS100 has a good half-life in dogs.
  • the polypeptide analogs disclosed herein have good solubility.
  • the Myristoyl-P1(37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 18 -COOH)-PAS100 has good solubility in mice.
  • the P1 in the polypeptide analogs disclosed herein has other acylation modifications except the ⁇ -amino acylation modification of Lys45(X 2 ), the polypeptide analogs lose activity.
  • the present disclosure also provides a polypeptide intermediate compound, comprising an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in SEQ ID NO: 10.
  • the polypeptide intermediate compound comprises the amino acid sequence shown in SEQ ID NO: 10.
  • the polypeptide intermediate compound has an amino acid sequence as shown in SEQ ID NO: 10.
  • C 14 is myristoyl.
  • the preparation method of the polypeptide analog of the present disclosure comprises the following steps: (a) preparing the peptide chain portion composed of amino acids in P1 and a modifying group for acylation modification; (b) performing a myristoylation reaction at the N-terminus of the peptide chain portion; (c) performing acylation modification on the ⁇ -amino group of the amino acid residue X2 of the peptide chain portion with the modifying group to obtain the polypeptide analog; and (d) isolating and purifying the polypeptide analog.
  • kits comprising a polypeptide analog or pharmaceutical composition of the present disclosure.
  • the kit further comprises instructions for use.
  • the kit may also include other materials required from a commercial and user perspective, such as other buffers, diluents, needles, syringes, etc.
  • Embodiment 1 A polypeptide analogue, whose general structural formula is C 14 -P 1 -U 1 ;
  • P1 contains the following amino acid sequence:
  • X 1 is selected from D-Ala, ⁇ -Ala, GABA, Aib, Abu, Arg, Asp, Asn, Cys, Glu, D-Glu, ⁇ -Glu, Gln, Gly, His, Ile, Leu, Pro, Phe, Ser, Tyr, Thr, Trp, Val or Met, preferably ⁇ -Ala, GABA, Aib, Abu, Arg or Cys, more preferably Arg;
  • X 2 is Lys, and its ⁇ -amino group has an acylated modification group;
  • C 14 is a myristoyl group at the N-terminus of P 1 ;
  • U1 is a PAS sequence connected to the C-terminus of P1 , wherein the PAS sequence consists of Pro, Ala and/or Ser and has 30-300 amino acid residues.
  • Embodiment 2 The polypeptide analog according to embodiment 1, wherein the structural formula of the modification group of X2 is:
  • p 6-20, 10-20, 14-20, 14-18 or 16-18,
  • n 0, 1, 2, 3, 4 or 5
  • n 0, 1, 2 or 3
  • Xaa is selected from D-Ala, ⁇ -Ala, GABA, Aib, Abu, Arg, Asp, Asn, Cys, D-Glu, ⁇ -Glu, Gln, Gly, His, Ile, Leu, Lys, Pro, Phe, Ser, Tyr, Thr, Trp, Val or Met,
  • R1 is -CH3 or -COOH
  • Wavy Lines represents the connection position of the modifying group to the ⁇ -amino group of X2 .
  • Embodiment 3 A polypeptide analog according to embodiment 2, wherein m is 0, 1, 2 or 3, preferably 0 or 2.
  • Embodiment 4 A polypeptide analog according to embodiment 2 or 3, wherein n is 0 or 1.
  • Embodiment 5 The polypeptide analog according to embodiment 2, wherein the modifying group has a structural formula shown in Formula 1 or Formula 2:
  • Embodiment 6 A polypeptide analog according to embodiment 5, wherein Xaa is selected from GABA, Aib, D-Ala, ⁇ -Ala, Asp, Cys, ⁇ -Glu, Gly, Pro or Phe, preferably ⁇ -Glu or Pro.
  • Embodiment 7 A polypeptide analog according to embodiment 5 or 6, wherein p is 6, 8, 10, 12, 14, 16, 18 or 20, preferably 16 or 18.
  • Embodiment 8 The polypeptide analog according to embodiment 1, wherein the modification group of X2 is selected from the following structural formula:
  • Embodiment 9 A polypeptide analog according to any one of embodiments 1-8, wherein the PAS sequence has 30-100 amino acid residues, preferably 30, 50 or 100 amino acid residues.
  • Embodiment 10 The polypeptide analog according to any one of embodiments 1-9, wherein Pro accounts for 10%-40% of the total number of amino acid residues in the PAS sequence.
  • Embodiment 11 A polypeptide analog according to any one of embodiments 1-10, wherein the PAS sequence comprises the amino acid sequence shown in SEQ ID NO: 2, 3, 4, 5, 6, 7 or 8.
  • Embodiment 12 A polypeptide analog according to any one of embodiments 1-11, wherein the amino acid sequence of the PAS sequence is as shown in SEQ ID NO: 2, 3, 4, 5, 6, 7 or 8.
  • Embodiment 13 The polypeptide analog according to embodiment 1, wherein the polypeptide analog is selected from the following structural formula:
  • C 14 is myristoyl; p is 6-20, 10-20, 14-20, 14-18 or 16-18, preferably 6, 8, 10, 12, 14, 16, 18 or 20;
  • Xaa is selected from D-Ala, ⁇ -Ala, GABA, Aib, Abu, Arg, Asp, Asn, Cys, D-Glu, ⁇ -Glu, Gln, Gly, His, Ile, Leu, Lys, Pro, Phe, Ser, Tyr, Thr, Trp, Val or Met, preferably GABA, Aib, D-Ala, ⁇ -Ala, Asp, Cys, ⁇ -Glu, Gly, Pro or Phe, more preferably ⁇ -Glu or Pro; and R 1 is -CH 3 or -COOH.
  • Embodiment 14 The polypeptide analog according to embodiment 1, wherein the polypeptide analog is selected from the following structural formula:
  • C 14 is myristoyl.
  • Embodiment 16 A pharmaceutical composition comprising the polypeptide analog according to any one of Embodiments 1-14, and a pharmaceutically acceptable carrier.
  • Embodiment 17 The pharmaceutical composition according to Embodiment 16, wherein the pharmaceutical composition is a liquid preparation.
  • Embodiment 19 The pharmaceutical composition according to Embodiment 16, wherein the pharmaceutical composition is a solid preparation.
  • Embodiment 22 Use of the polypeptide analogue of any one of Embodiments 1-14 or the pharmaceutical composition of any one of Embodiments 16-20 in the preparation of a medicament for treating patients infected with HBV and/or HDV.
  • Embodiment 24 A method of treating a patient infected with HBV and/or HDV, comprising administering to the patient a therapeutically effective amount of the polypeptide analog of any one of embodiments 1-14 or the pharmaceutical composition of any one of embodiments 16-20.
  • Embodiment 27 A myristoylated polypeptide intermediate compound, the structure of which is shown below:
  • the compounds of the present disclosure may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present disclosure (including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof such as racemic mixtures) are constituents of the present disclosure.
  • the compounds of the present disclosure containing asymmetric carbon atoms may be isolated in optically pure form or in racemic form. Optically pure forms may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • (a certain group) n means that there are n such groups in the moiety.
  • (AEEA) n or (Xaa) n as used herein means that It means that there are n linked AEEA groups or Xaa groups in the moiety.
  • C 14 refers to Myristoyl, also known as myristoyl, whose structure is -CO-(CH 2 ) 12 -CH 3 .
  • PAS sequence is a polypeptide fragment composed of three amino acids: proline, alanine, and serine, which is highly soluble under physiological conditions, has no charge, and exhibits a random coil structure. When a PAS sequence has 0 amino acid residues, it means that the PAS sequence is missing.
  • pharmaceutically acceptable refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compounds described herein. Such substances do not cause undesirable biological effects when administered to an individual or do not interact in a deleterious manner with any component of the composition in which they are contained.
  • pharmaceutically acceptable salt includes salts formed by alkali ions and free acids or salts formed by acid ions and free bases, for example, including hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formates, acetates, trifluoroacetates, fumarates, oxalates, maleates, citrates, tartrates, succinates, methanesulfonates, benzoates, benzenesulfonates or p-toluenesulfonates, preferably hydrochloride, hydrobromide, sulfate, formates, acetates, trifluoroacetates, fumarates, maleates, methanesulfonates, p-toluenesulfonates, sodium salts, potassium salts, ammonium salts, amino acid salts, etc.
  • the pharmaceutically acceptable salt of the polypeptide analogs disclosed herein is the acetate
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coating materials, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, etc. and combinations thereof, which are well known to those skilled in the art (Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except for carriers that are incompatible with the active ingredient, any conventional carrier is contemplated for use in therapeutic or pharmaceutical compositions.
  • treatment refers to an attempt to alter the natural course of a disease in a treated individual, and may be a clinical intervention performed for prevention or during the course of clinical pathology. Desired effects of treatment include, but are not limited to, preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, ameliorating or palliating the disease state, and regression or improved prognosis.
  • subject includes any human or non-human animal.
  • non-human animal includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • the subject according to the present disclosure is a human.
  • the terms “patient” or “subject” can be used interchangeably.
  • the present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, etc., respectively.
  • Certain isotopically labeled compounds of the present invention can be used in compound and/or substrate tissue distribution analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H)
  • can provide certain therapeutic advantages e.g., increased in vivo half-life or reduced dosage requirements resulting from higher metabolic stability, and therefore may be preferred in some cases.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present invention can generally be prepared by replacing an isotopically labeled reagent with an isotopically labeled reagent by the following procedures similar to those disclosed in the schemes and/or embodiments below.
  • phenylalanine is Phe or F
  • leucine is Leu or L
  • isoleucine is Ile or I
  • methionine is Met or M
  • valine is Val or V
  • serine is Ser or S
  • proline is Pro or P
  • threonine is Thr or T
  • alanine is Ala or A
  • tyrosine is Tyr or Y
  • histidine is His or H
  • glutamine is Gln or Q
  • asparagine is Asn or N
  • lysine is Lys or K
  • aspartic acid is Asp or D
  • glutamic acid is Glu or E
  • cysteine is Cys or C
  • tryptophan Trp or W
  • arginine is Arg or R
  • glycine is Gly or G.
  • D-alanine is D-Ala
  • D- Glutamic acid is D-Glu
  • ⁇ -alanine i.e. 3-aminopropionic acid
  • 4-aminobutyric acid is GABA
  • 2-aminoisobutyric acid is Aib
  • 2-aminobutyric acid is Abu.
  • the ⁇ -carboxyl group participates in the formation of peptide bonds while the ⁇ -carboxyl group is a free carboxyl group, which has the following structure:
  • “about” means within the acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” may mean within 1 or more than 1 standard deviation as practiced in the art. Alternatively, “about” may mean a range of up to ⁇ 5%, such as fluctuations within ⁇ 2%, within ⁇ 1%, or within ⁇ 0.5% of a given specific numerical range. When a specific value is given in the present disclosure or claims, unless otherwise indicated, the meaning of "about” should be considered to be within the acceptable error range for that specific value. In this document, unless otherwise indicated, all values of drug doses, times, step parameters, or conditions are modified by "about” by default.
  • 2-CTC 2-chlorotrityl chloride
  • Fmoc-Glu-OMe (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-methoxy-5-oxopentanoic acid
  • Fmoc-AEEA-OH [2-[2-(Fluorenylmethoxycarbonylamino)ethoxy]ethoxy]acetic acid
  • Fmoc-Gly-OH Fmoc-Gly-OH
  • Fmoc-Arg(Pbf)-OH N-Fmoc-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine
  • Fmoc-Ser(tBu)-OH N-Fmoc-O-tert-butyl-L-serine
  • Fmoc-Pro-OH fluorenylmethoxycarbonyl-L-
  • PBS contains 0.27 g/L potassium dihydrogen phosphate (KH 2 PO 4 ), 2.85 g/L disodium hydrogen phosphate dodecahydrate (Na 2 HPO 4 ⁇ 12H 2 O), 8.5 g/L sodium chloride (NaCl) and 0.2 g/L potassium chloride (KCl).
  • Example 1 Preparation of Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 16 -COOH)-PAS100
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 16 -COOH)-PAS100 is as follows:
  • Fmoc-Glu-OMe (CAS No.: 145038-49-9), Fmoc-AEEA-OH (CAS No.: 166108-71-0), octadecanediolatoic acid mono-tert-butyl ester (CAS No.: 843666-40-0), myristic acid succinimidyl ester (Hanxiang Biotechnology, CAS No.: 69888-86-4).
  • Synthesis reagents HOBt, DIC, DMF, DCM, PIP, DIEA.
  • Activating reagents DCC, HOSU.
  • the crude product was purified using a Waters 600 semi-preparative high performance liquid chromatograph with the gradient elution parameters shown in Table 1: the chromatographic column was Kromasil 300-10-C 4 10*250 mm, the flow rate was 5 mL/min, the detection wavelengths were 215 nm and 280 nm, the mobile phase A was 0.5% HAC (v/v) aqueous solution, and the mobile phase B was 0.5% HAC (v/v) acetonitrile solution.
  • the collected purified product was analyzed using the gradient elution parameters shown in Table 2: the chromatographic column was Kromasil 100-3.5-C 4 4.6*150 mm, the flow rate was 1 mL/min, the detection wavelength was 215 nm, the mobile phase A was 0.05% TFA (v/v) aqueous solution, and the mobile phase B was 0.05% TFA (v/v) acetonitrile solution.
  • the target component with a purity greater than 90% was collected, acetonitrile was removed by vacuum distillation, and vacuum freeze-dried.
  • the crude product of the above-mentioned polypeptide analog was purified using a Waters 600 semi-preparative high performance liquid chromatograph with the gradient elution parameters shown in Table 1: the chromatographic column was Kromasil 300-10-C 4 10*250mm, the flow rate was 5mL/min, the detection wavelengths were 215nm and 280nm, the mobile phase A was 0.5% HAC (v/v) aqueous solution, and the mobile phase B was 0.5% HAC (v/v) acetonitrile solution.
  • the collected purified peptide analogs were analyzed using the gradient elution parameters shown in Table 2: the chromatographic column was Kromasil 100-3.5-C 4 4.6*150 mm, the flow rate was 1 mL/min, the detection wavelength was 215 nm, the mobile phase A was 0.05% TFA (v/v) aqueous solution, and the mobile phase B was 0.05% TFA (v/v) acetonitrile solution.
  • the target component with a purity greater than 90% was collected, acetonitrile was removed by reduced pressure distillation, and vacuum freeze-dried.
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 6 -COOH)-PAS100 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 8 -COOH)-PAS100 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 10 -COOH)-PAS100 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 12 -COOH)-PAS100 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 14 -COOH)-PAS100 is as follows:
  • Example 7 Preparation of Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 18 -COOH)-PAS100
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 18 -COOH)-PAS100 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 6 -CH 3 )-PAS100 is as follows:
  • the fatty acid used to synthesize the acylation-modified modifying group is: n-octanoic acid.
  • n-octanoic acid Take 0.1 mmol of n-octanoic acid, about 0.15 mmol of HOSU, and about 0.12 mmol of DCC, add about 5 mL of dichloromethane, react at room temperature for 1-2 hours, distill under reduced pressure to remove dichloromethane, and dissolve with DMF to obtain an acylated activated ester solution.
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 16 -CH 3 )-PAS100 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 18 -CH 3 )-PAS100 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 6 -CH 3 )-PAS30 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 8 -CH 3 )-PAS30 is as follows:
  • Example 17 Preparation of Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 10 -CH 3 )-PAS30
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 10 -CH 3 )-PAS30 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 12 -CH 3 )-PAS30 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 14 -CH 3 )-PAS30 is as follows:
  • Example 20 Preparation of Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 16 -CH 3 )-PAS30
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 16 -CH 3 )-PAS30 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -CO-(CH 2 ) 18 -CH 3 )-PAS30 is as follows:
  • Example 22 Preparation of Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 6 -COOH)-PAS30
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 6 -COOH)-PAS30 is as follows:
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 8 -COOH)-PAS30 is as follows:
  • Example 24 Preparation of Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 10 -COOH)-PAS30
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 10 -COOH)-PAS30 is as follows:
  • Example 25 Preparation of Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 12 -COOH)-PAS30
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 12 -COOH)-PAS30 is as follows
  • Example 26 Preparation of Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 14 -COOH)-PAS30
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 14 -COOH)-PAS30 is as follows:
  • Example 27 Preparation of Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 16 -COOH)-PAS30
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 16 -COOH)-PAS30 is as follows:
  • Example 28 Preparation of Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 18 -COOH)-PAS30
  • Myristoyl-P 1 (37Arg, Lys45- ⁇ -AEEA-AEEA- ⁇ -Glu-CO-(CH 2 ) 18 -COOH)-PAS30 is as follows:
  • Myristoyl-P 1 (37Arg)-PAS100 is as follows:
  • 0.5mmol P 1 (37Arg)-PAS100 was dissolved in 20mmol/L PBS (pH 7.4) to a final concentration of 5mg/mL, and an equal volume of acetonitrile was added. 10 times the volume of acetonitrile solution containing myristoyl acid succinimidyl ester (2mg/mL) was slowly added dropwise to the above solution, and the reaction was stirred at room temperature for 2 hours. Then, the pH was adjusted to 4.0 with 0.1mol/L hydrochloric acid to terminate the reaction to obtain a crude product Myristoyl-P 1 (37Arg)-PAS100.
  • the crude product was purified by semi-preparative high performance liquid chromatography using the gradient elution parameters shown in Table 1: the chromatographic column was Kromasil 300-10-C 4 10*250 mm, the flow rate was 5 mL/min, the detection wavelengths were 215 nm and 280 nm, the mobile phase A was 0.5% HAC (v/v) aqueous solution, and the mobile phase B was 0.5% HAC (v/v) acetonitrile solution.
  • the collected purified product was analyzed using the gradient elution parameters shown in Table 2: the chromatographic column was Kromasil 100-3.5-C 4 4.6*150 mm, the flow rate was 1 mL/min, the detection wavelength was 215 nm, the mobile phase A was 0.05% TFA (v/v) aqueous solution, and the mobile phase B was 0.05% TFA (v/v) acetonitrile solution.
  • the target component with a purity greater than 90% was collected, acetonitrile was removed by vacuum distillation, and vacuum freeze-dried.
  • Myristoyl-P 1 (37Arg)-PAS30 is as follows:
  • Fmoc-Gly-Wang Resin (Xishi Biotechnology Co., Ltd.), substitution value is 0.29mmol/g;
  • Fmoc-Gly-OH (CAS No.: 29022-11-5), Fmoc-Arg(Pbf)-OH (CAS No.: 154445-77-9), Fmoc-Ser(tBu)-OH (CAS No.: 71989-33-8), Fmoc-Pro-OH (CAS No.: 71989-31-6), Fmoc-Ala-OH (CAS No.: 35661-39-3), Fmoc-Ile-OH (CAS No.: 71989-23-6), Fmoc-Leu-OH (CAS No.: 35661-60-0), Fmoc-Trp(Boc)-OH (CAS No.: 143824-78-6), Fmoc-Gln(Trt)-OH (CAS No.: 132327-80-1), Fmoc- Val-OH (CAS No.: 68858-20-8), Fmoc-Phe-OH (CAS No.: 35661-40-6), Fmoc-Glu(OtBu)-OH (CAS
  • Synthesis reagents HOBt, DIC, DMF, DCM, PIP, DIEA.
  • CSIO-BIO peptide synthesizer Waters 600 semi-preparative high performance liquid chromatograph, Beckman centrifuge, BUCHI vacuum distillation apparatus.
  • the crude product was purified by semi-preparative high performance liquid chromatography using the gradient elution parameters shown in Table 1: the chromatographic column was Kromasil 300-10-C 4 10*250 mm, the flow rate was 5 mL/min, the detection wavelengths were 215 nm and 280 nm, the mobile phase A was 0.5% HAC (v/v) aqueous solution, and the mobile phase B was 0.5% HAC (v/v) acetonitrile solution.
  • the collected purified product was analyzed using the gradient elution parameters shown in Table 2: the chromatographic column was Kromasil 100-3.5-C 4 4.6*150 mm, the flow rate was 1 mL/min, the detection wavelength was 215 nm, the mobile phase A was 0.05% TFA (v/v) aqueous solution, and the mobile phase B was 0.05% TFA (v/v) acetonitrile solution.
  • the target component with a purity greater than 90% was collected, acetonitrile was removed by vacuum distillation, and vacuum freeze-dried.
  • Fmoc-Gly-OH (CAS No.: 29022-11-5), Fmoc-Arg(Pbf)-OH (CAS No.: 154445-77-9), Fmoc-Ser(tBu)-OH (CAS No.: 71989-33-8), Fmoc-Pro-OH (CAS No.: 71989-31-6), Fmoc-Ala-OH (CAS No.: 35661-39-3), Fmoc-Ile-OH (CAS No.: 71989-23-6), Fmoc-Leu-OH (CAS No.: 35661-60-0), Fmoc-Trp(Boc)-OH (CAS No.: 143824-78-6), Fmoc-Gln(Trt)-OH (CAS No.: 132327-80-1), Fmoc- Val-OH (CAS No.: 68858-20-8), Fmoc-Phe-OH (CAS No.: 35661-40-6), Fmoc-Glu(OtBu)-OH (CAS
  • Synthesis reagents HOBt, DIC, DMF, DCM, PIP, DIEA
  • CSIO-BIO peptide synthesizer Waters 600 semi-preparative high performance liquid chromatograph, Beckman centrifuge, BUCHI vacuum distillation apparatus.
  • the crude product was purified by semi-preparative HPLC using the gradient elution parameters shown in Table 1: the chromatographic column was Kromasil 300-10-C 4 10*250 mm, the flow rate was 5 mL/min, the detection wavelengths were 215 nm and 280 nm, and the mobile phase A was 0.5% HAC (v/v) aqueous solution, and mobile phase B was 0.5% HAC (v/v) acetonitrile solution.
  • the collected purified product was analyzed using the gradient elution parameters shown in Table 2: the chromatographic column was Kromasil 100-3.5-C 4 4.6*150 mm, the flow rate was 1 mL/min, the detection wavelength was 215 nm, the mobile phase A was 0.05% TFA (v/v) aqueous solution, and the mobile phase B was 0.05% TFA (v/v) acetonitrile solution.
  • the target component with a purity greater than 90% was collected, acetonitrile was removed by vacuum distillation, and vacuum freeze-dried.
  • HepG2NTCP cells were plated at a density of 2 ⁇ 10 5 /mL, 100 ⁇ L/well, and DME maintenance medium containing 2.5% DMSO and 5% FBS was added the next day for 24 hours of induction culture.
  • the HBV virus derived from the supernatant of HepAD38 cells was diluted to an infection dose of 100 MOI, and the dilution medium was DMEM medium containing 2.5% DMSO and 4% PEG8000.
  • the peptide analogs to be tested and the control Myrcludex B were diluted to 1000nmol/L, 200nmol/L, 40nmol/L, 8nmol/L, 1.6nmol/L, 0.32nmol/L, 0.064nmol/L, and 0.0128nmol/L, respectively, with a total of 8 dilutions, and the dilution medium was DMEM medium containing 2.5% DMSO and 4% PEG8000.
  • the infection blocking group different concentrations of diluted compounds were added 30 minutes in advance, 100 ⁇ L/well, and then the diluted virus was added, 100 ⁇ L/well, and gently blown 4-6 times. Centrifuge at room temperature for 30 minutes at 1000 rpm.
  • Example 34 In vivo pharmacokinetics study of HB-38 in beagle dogs
  • Beagle dogs (weight 9-11 kg) were randomly divided into two groups, each with 2 dogs, and injected subcutaneously with Myrcludex B and HB-38 at a dose of 1 mg/kg.
  • test animals (beagle dogs) were fasted for 12 h before administration and given food 4 h after administration. They were allowed to drink water freely before, during and after the experiment.
  • the subcutaneous injection exposure of the disclosed compound was evaluated by in vivo pharmacokinetic experiments in beagle dogs, and the peak concentration ( Cmax ), time to peak ( Tmax ), area under the drug-time curve (AUC (0-264h) and AUC ( 0- ⁇ )), elimination half-life (t1 /2 ) and mean residence time (MRT ( 0-264h )) were calculated .
  • the above pharmacokinetic parameters are shown in Table 4.
  • the plasma concentration-time curve is shown in Figure 1.
  • the experimental results showed that the pharmacokinetic behaviors of beagle dogs after subcutaneous injection of 1 mg/kg Myrcludex B and HB-38 were significantly different.
  • the C max and exposure AUC (0-t) of the HB-38 group were significantly higher than those of the control group Myrcludex B, and the half-life of the HB-38 group was significantly longer than that of the control group Myrcludex B.

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Abstract

L'invention concerne un analogue de polypeptide antiviral, une composition pharmaceutique contenant l'analogue de polypeptide antiviral, un procédé de préparation et son utilisation. L'analogue de polypeptide antiviral présente une demi-vie satisfaisante et une solubilité satisfaisante tout en maintenant une bonne activité inhibitrice contre des infections virales.
PCT/CN2023/116435 2023-09-01 2023-09-01 Analogue de polypeptide antiviral Pending WO2025043696A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014464A1 (fr) * 1992-12-22 1994-07-07 Allelix Biopharmaceuticals Inc. Compositions synergiques contenant un analogue de nucleoside antiviral et un oligopeptide antiviral
CN101045156A (zh) * 2006-03-29 2007-10-03 刘宏利 特异靶向性药物及其用途
CN103421094A (zh) * 2012-05-24 2013-12-04 上海医药工业研究院 一种具有epo类似活性的多肽化合物
CN108367047A (zh) * 2015-12-16 2018-08-03 鲁普莱希特-卡尔斯-海德堡大学 环状ntcp靶向肽及其作为进入抑制剂的应用
CN108721599A (zh) * 2017-04-18 2018-11-02 Myr有限公司 使用htcp抑制剂的疗法
WO2021231648A2 (fr) * 2020-05-12 2021-11-18 Gigagen, Inc. Agents thérapeutiques contre le cancer comprenant une chimiokine ou son analogue
CN116333092A (zh) * 2021-12-23 2023-06-27 正大天晴药业集团股份有限公司 特立帕肽脂酰化衍生物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014464A1 (fr) * 1992-12-22 1994-07-07 Allelix Biopharmaceuticals Inc. Compositions synergiques contenant un analogue de nucleoside antiviral et un oligopeptide antiviral
CN101045156A (zh) * 2006-03-29 2007-10-03 刘宏利 特异靶向性药物及其用途
CN103421094A (zh) * 2012-05-24 2013-12-04 上海医药工业研究院 一种具有epo类似活性的多肽化合物
CN108367047A (zh) * 2015-12-16 2018-08-03 鲁普莱希特-卡尔斯-海德堡大学 环状ntcp靶向肽及其作为进入抑制剂的应用
CN108721599A (zh) * 2017-04-18 2018-11-02 Myr有限公司 使用htcp抑制剂的疗法
WO2021231648A2 (fr) * 2020-05-12 2021-11-18 Gigagen, Inc. Agents thérapeutiques contre le cancer comprenant une chimiokine ou son analogue
CN116333092A (zh) * 2021-12-23 2023-06-27 正大天晴药业集团股份有限公司 特立帕肽脂酰化衍生物

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