EP-4737473-A1 - NOVEL COMPLEMENT INHIBITOR AND PREPARATION, USE AND PRODUCT THEREOF

Abstract

Provided in the present invention are a novel complement inhibitor, and a preparation, the use and a product thereof, which belong to the field of molecular medicine. The portion having complement inhibitory activity comprises a cyclic peptide and a pharmaceutically acceptable salt thereof. The cyclic peptide is shown as general formula I: R1-ICXaa 3 -Xaa 4 -QD-Xaa 7 -G-Xaa 9 -HRCT-R2, wherein Xaa 7 and Xaa 9 are selected from uncommon amino acids, and Xaa 3 and Xaa 4 include at least one uncommon amino acid. When the cyclic peptide provided in the present invention is used as an active ingredient of the complement inhibitor, the cyclic peptide has good affinity to a C3 protein, has good pharmacokinetic properties, and has good application prospects.

Inventors

• DAI, PENG
• WANG, YE

Assignees

• Liu, Xiaorong

Dates

Publication Date

20260506

Application Date

20240620

Claims (18)

1. A complement inhibitor, wherein an active ingredient of the complement inhibitor comprises a cyclic peptide or a pharmaceutically acceptable salt of the cyclic peptide, wherein the cyclic peptide is shown in a general formula I: R1-IC-Xaa 3 -Xaa 4 -QD-Xaa 7 -G-Xaa 9 -HRCT-R2; Xaa 7 and Xaa 9 are selected from uncommon amino acids, at least one of Xaa 3 or Xaa 4 is an uncommon amino acid; R1 and R2 are modifying groups; the general formula I is cyclized via a disulfide bridge formed between Cys-2 and Cys-12.
2. The complement inhibitor according to claim 1, wherein Xaa 3 is selected from common amino acids or uncommon amino acids; Xaa 4 is selected from uncommon amino acids; Xaa 7 is selected from either 2Nal or 5F-Trp; Xaa 9 is selected from either Aib or Pip.
3. The complement inhibitor according to claim 2, wherein Xaa 3 is selected from any one of V, Y, or Abu; Xaa 4 is selected from any one of 2Nal, W(CH 3 ), Bpa, or AzaTrp; Xaa 7 is selected from either 2Nal or 5F-Trp; Xaa 9 is selected from either Aib or Pip.
4. The complement inhibitor according to claim 1, wherein R1 is selected from any one of hydrogen, acetyl, methoxy, PEG or carboxyl, and R2 is selected from amino.
5. The complement inhibitor according to claim 4, wherein R1 is selected from acetyl group, and R2 is selected from amino group.
6. The complement inhibitor according to claim 1, wherein R1 and R2 are selected from amino acids or variants of amino acids.
7. The complement inhibitor according to claim 6, wherein R1 and R2 are independently selected from tyrosine or isoleucine respectively.
8. The complement inhibitor according to claim 7, wherein R1 is selected from isoleucine, and R2 is selected from tyrosine.
9. The complement inhibitor according to any one of claims 6-8, wherein R1 and R2 form an amide bond to loop polypeptide from end to end.
10. The complement inhibitor according to claim 1, wherein the active ingredient of the complement inhibitor is selected from one or more of SEQ ID NO.1- SEQ ID NO.6.
11. The complement inhibitor according to claim 1, wherein the active ingredient of the complement inhibitor is an optimized product with the general formula I; the optimization comprises one or more of PEGylation, conjugation, homo-multimerization, hetero-multimerization, amino acid chirality optimization, incorporation of hydrophilic/charged residues, addition of cell-penetrating peptides, and in-chain N-methylation.
12. The complement inhibitor according to claim 11, wherein the optimization occurs at R1 or R2 or backbone amino acids; preferably, the optimization is the incorporation of hydrophilic/charged residues at R2, and more preferably, the optimization is the incorporation of one or more K or R residues.
13. The complement inhibitor according to claim 11, wherein the PEGylation occurs at R1; and the in-chain N-methylation occurs at Xaa 9 .
14. A method for preparing the complement inhibitor according to any one of claims 1-13 based on the amino acid sequence.
15. Use of the complement inhibitor according to any one of claims 1-13 in preparation of a drug for treating complement-mediated disorders.
16. The use according to claim 15, wherein the complement-mediated disorders comprise any one or a combination of ophthalmic diseases, glomerulonephritis, systemic lupus erythematosus, streptococcus pneumoniae infection, skin rashes, inflammation, paroxysmal nocturnal hemoglobinuria, atypical haemolytic uraemic syndrome, complement-mediated hemolysis, adult respiratory distress syndrome, heart diseases, or complement-mediated injury; the inflammation comprises periodontitis; the ophthalmic diseases comprise any one or a combination of macular degeneration, choroidal neovascularization, retinal neovascularization, and geographic atrophy; the drug is preferably an injection, more preferably a local injection, and most preferably a subcutaneous injection or intravenous injection; the drug is preferably an ophthalmic preparation, more preferably an intravitreal injection or ophthalmic drops.
17. A drug comprising the complement inhibitor according to any one of claims 1-13, or a salt, tandem, or multimer of the complement inhibitor.
18. The drug according to claim 17, wherein the drug comprises one or more of SEQ ID NO.1-SEQ ID NO.6.

Description

TECHNICAL FIELD The disclosure belongs to the field of molecular medicine, and specifically to novel complement inhibitor and preparation, application and products thereof. BACKGROUND ART Complement refers to a group of globulins with enzyme-like activity after activation, present in the blood, tissue fluid, and cell membrane surfaces of humans and animals. The complement system is an important component of innate immunity and participates in immune regulation and immune damaging reactions in the human body. Composed of more than 30 soluble proteins and membrane-bound proteins, the complement system has three main activation pathways: the classical pathway, the alternative pathway, and the lectin activation pathway. Complement exists in an inactive state in plasma and exhibits biological activity upon activation. It can eliminate immune complexes through cytolysis, opsonization, phagocytosis, and mediation of inflammatory responses, thereby exerting corresponding biological functions. The three activation pathways of the complement system c are centered around the formation of C3 convertase and C5 convertase. By cleaving C3 and C5 to produce corresponding bioactive fragments, the complement response is further amplified. These fragments modify the target surface and can promote phagocytosis, inflammation, immune regulation, and other processes. Among them, the process from contact with the activating agent to the generation of C3 convertase (and cleavage of C3) can be regarded as the front-end reactions of these activation pathways. Although the front-end reactions of these activation pathways are different, they share a common terminal pathway, i.e., the generation of C5 convertase. C5 is cleaved to form C5b fragments, which sequentially react with C6, C7, C8, and C9 to ultimately form the membrane attack complex (MAC), exerting a cytolytic effect. Although the complement system plays an important role in human immunity, inappropriate or excessive complement activation is the root cause or contributing factor of many serious diseases. The discovery of complement inhibitors has provided a promising research direction for the treatment of related diseases. Complement drugs have been approved for marketing in diseases such as paroxysmal nocturnal hemoglobinuria (PNH) and geographic atrophy caused by age-related macular degeneration. As known from the three activation pathways of the complement system, inhibiting C3 can control the early reactions of the activation pathways, so the development of C3 complement inhibitors has broad application prospects. As the most abundant complement protein in human serum, C3 consists of α and β chains. Activated C3 is cleaved into fragments with important biological activities: C3a, C3b, iC3a, C3d, etc. C3 contains 41 exons and has an abundant structure providing multiple different ligand-binding sites, such as the conserved domains disclosed in the prior art: α2-macroglobulin domain (A2M), C3a anaphylatoxin domain, etc. (Zan Qi, Liu Xin, Pang Yue, et al., Research progress of complement C3 structure and function [J], China Journal of Immunology, 2014(04): 549-553, DOI:10.3969/j.issn.1000-484X.2014.04.031.), which are important in immune surveillance and immune response pathways. Compstatin is the first discovered C3 complement inhibitor, a thirteen-residue cyclic peptide that can bind both C3a and C3b and prevent the cleavage of native C3 by C3 convertase. This cyclic peptide is a molecule composed of a polar part and a non-polar part. The polar part includes a type I β-turn, and the non-polar part includes a disulfide bond. The prior art has verified that the four residues of the β-turn and the disulfide bond of the surrounding hydrophobic cluster play important roles in the inhibitory activity of C3 complement inhibitor. Based on the initially disclosed compstatin structure, the prior art has continuously optimized it to improve its pharmaceutical properties. For example, the optimized compstatin analog Ac-ICVW(CH3)QDWGAHRCT-NH2 (C-C) has an activity 16 times that of the parent, as recorded in "Morikis D, Soulika A M, Mallik B, et al. Improvement of the anti-C3 activity of compstatin using rational and combinatorial approaches". Empaveli (pegcetacoplan) is the first marketed C3 complement inhibitor drug, a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that specifically binds C3a and C3b. Currently, Empaveli has been approved for indications including paroxysmal nocturnal hemoglobinuria (PNH) and geographic atrophy caused by dry macular degeneration. Other optimization methods of compstatin disclosed in the prior art further include methylation on the peptide backbone and substitution at flanking positions, leading to the development of a series of compstatin analogs with improved potency (Qu et al., 2011, Molecular Immunology 48: 481-489; WO2010/127336). These modifications have resulted in compstatin analogs exhibiting binding affinity superior to