CN-121971584-A - Application of marine small molecular peptide and active variant thereof in preparation of skin disease drugs

Abstract

The invention belongs to the technical field of biological medicines, and in particular relates to application of a marine small molecular peptide and an active variant thereof in preparation of a skin disease medicine, wherein the marine small molecular peptide and the active variant thereof can effectively inhibit keratinocyte pan-apoptosis induced by TNF-alpha and IFN-gamma, and block PANoptosome complex formation through multi-target synergistic effect, reduce oxidative stress and stabilize mitochondria, so that a skin inflammatory cell death network is inhibited from the source. The variant is identical to the peptide in high sequence, retains the activity of inhibiting cell ubiquitination, and has enhanced stability, skin permeability, in vivo half-life or drug effect. Based on the action mechanism, the peptide and the variant thereof can be used for preparing medicines for preventing and treating refractory skin diseases such as epidermis necrosis and lysis, psoriasis, atopic dermatitis, cutaneous lupus erythematosus, lichen planus and the like. The invention also provides a composition containing the peptide or the variant thereof, and dosage forms comprise external preparations and injections.

Inventors

• CHEN HUA
• CAI BINGNA
• PAN JIANYU
• CHEN DEKE
• WAN PENG
• SUN HUILI

Assignees

• 中国科学院南海海洋研究所

Dates

Publication Date

20260505

Application Date

20260209

Claims (10)

1. 1. Use of a marine small molecule peptide, an active variant thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of a skin disorder, characterized in that the marine small molecule peptide comprises an amino acid sequence as shown in SEQ ID No. 1.
2. 2. The use according to claim 1, wherein the skin disease is selected from the group consisting of epidermolysis necrotica, psoriasis, atopic dermatitis, cutaneous lupus erythematosus and lichen planus.
3. 3. The use according to claim 1, wherein the active variant has at least 70% sequence identity with the amino acid sequence shown in SEQ ID No.1 and retains the activity of inhibiting the ubiquitination of keratinocytes.
4. 4. The use according to claim 3, wherein the retention of the activity of inhibiting keratinocyte ubiquitination is such that the effect of the active variant on promoting cell survival is not less than 70% of the peptide represented by SEQ ID No.1 at equimolar concentrations in a model of keratinocyte ubiquitination induced by a combination of TNF- α and IFN- γ.
5. 5. The use according to claim 3, wherein the active variant comprises one or more modifications selected from the group consisting of: (a) One or more amino acid residues are substituted with their corresponding D-type amino acid residues; (b) One or more amino acid residues are substituted with a conservative amino acid selected from the group consisting of substitution of glycine with alanine or sarcosine, substitution of glutamic acid with aspartic acid, substitution of proline with an N-methylated amino acid, substitution of tryptophan with phenylalanine or tyrosine; (c) An N-terminally acetylated, acylated or linked cell penetrating peptide sequence; (d) The C-terminus is amidated; (e) One or more amide bonds in the peptide backbone are N-methylated; (f) Forming an intramolecular cyclization structure, said cyclization being achieved by head-to-tail linkages, inter-side chain disulfide linkages, lactam linkages, or click chemistry linkages; (g) Covalently linking 1-multiple polyethylene glycol molecules with molecular weight of 2kDa-20 kDa.
6. 6. The use according to claim 1, wherein the marine small molecule peptide or active variant thereof inhibits keratinocyte pan-apoptotic pathway by multi-target action.
7. 7. The use according to claim 6, wherein the multi-target effect comprises one or more of the following: (a) Down-regulating expression or activity of one or more proteins in ZBP1, AIM2, NLRP3, NLRP12, NLRC5, ASC, FADD; (b) Inhibiting phosphorylation activation of RIPK1 and/or RIPK 3; (c) Reducing the level or activity of one or more proteins of CLEAVED CASPASE-3, CLEAVED CASPASE-8, bax, cytochrome C; (d) Inhibiting phosphorylation of MLKL; (e) Reduce the level or activity of one or more proteins in CLEAVED CASPASE-1, GSDMD-N, GSDME-N.
8. 8. The use according to claim 1, wherein the medicament is an external preparation or an injection preparation, the external preparation is selected from a cream, a gel, an ointment, a solution or a spray, and the injection preparation is selected from a lyophilized powder injection or a prefilled injection.
9. 9. The use according to claim 8, wherein the marine small molecule peptide or the active variant thereof is contained in an amount of 0.3125ppm to 20000ppm in the external preparation or the injectable preparation.
10. 10. The use according to claim 8, wherein the freeze-dried powder injection comprises a lyoprotectant selected from mannitol or sucrose.

Description

Application of marine small molecular peptide and active variant thereof in preparation of skin disease drugs Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to application of a marine small molecular peptide and an active variant thereof in preparation of skin disease medicines. Background The skin is used as the largest organ and the first immune barrier of the human body, and various chronic inflammatory and autoimmune skin diseases (such as epidermonecrobiosis, psoriasis, atopic dermatitis, cutaneous lupus erythematosus, lichen planus and the like) become a major medical problem to be solved in clinical urgent need due to the characteristics of Cheng Qianyan, easy recurrence, treatment resistance and the like. Although clinical manifestations of the diseases are different, the core pathological characteristics are highly consistent, namely, the synergistic overexpression of pro-inflammatory cytokines such as local tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) of skin lesions triggers abnormal death of keratinocytes, forms malignant circulation of 'inflammation-cell death-inflammation amplification', and finally leads to skin tissue injury and dysfunction. The existing clinical treatment means (such as glucocorticoid, immunosuppressant, single cytokine targeting biological agent and the like) have remarkable limitations that either an action target point is positioned at the upstream of a ubiquitously apoptotic pathway or a parallel pathway, a core link of abnormal death of keratinocytes cannot be directly interfered, or the problems of limited response rate, remarkable side effects (such as infection risk and skin atrophy) after long-term use, easiness in drug resistance and the like exist. Therefore, the development of a novel drug which can precisely target the abnormal death core pathway of keratinocytes, has high safety and clear mechanism is an urgent need in the current skin disease treatment field. Recent studies revealed that TNF- α and IFN- γ co-induced ubiquity (PANoptosis) is a key form of abnormal death of keratinocytes, a process initiated by an upstream sensor such as ZBP1, and three death pathways of pyro-apoptosis, apoptosis and necrotic apoptosis are integrated by assembling PANoptosome complex, which ultimately leads to cell disintegration and inflammatory factor release. Although the prior studies have clarified the core role of ZBP 1-mediated PANoptosome pathway in skin injury, no drug capable of directly, efficiently and safely inhibiting the pathway has been found, and particularly, candidate molecules which are derived from natural marine organisms, have definite structures and excellent patentability are lacking, which provides a key technical gap for the development of the invention. The marine biological resource is an important source of novel active molecules, the applicant prior patent (CN202410696181. X) discloses a marine small molecular peptide containing an amino acid sequence GGEGPPW, which is used for preventing and treating skin sunburn, the action mechanism is based on antioxidant activity of scavenging free radicals, the physical skin injury caused by ultraviolet rays is only aimed at, the important difference exists between the pathological mechanism, the treatment target and the action target of the invention, although the TNF-alpha/IFN-gamma induced pan-apoptosis pathway exists in part of inflammatory diseases, the skin diseases (such as psoriasis and epidermis necrosis lysis) and the pathological microenvironment of skin sunburn exist in the essential difference, namely sunburn is initiated by physical injury induced by ultraviolet rays, the inflammatory factor release is mainly IL-1 beta and TNF-alpha, and no autoimmune component participates, the diseases such as psoriasis and atopic dermatitis are mainly immune imbalance, the specific inflammatory shaft activation of IL-23/IL-17 is accompanied, and the pan-forming cell apoptosis signals are completely different from the amplification threshold values of the panned by the panned skin. The prior art does not disclose that the pan-apoptosis inhibitor can be applied across physical injury and immune diseases, nor suggest that the pan-apoptosis inhibition activity of the marine small molecule peptide of the invention can cover skin diseases of different pathological types, and application of the peptide and variants thereof to other diseases other than skin sunburn requires independent target spot verification, drug delivery system optimization and pharmacodynamics evaluation. In summary, aiming at the technical defect that the prior therapy cannot accurately interfere with the keratinocyte pan-apoptosis core pathway and the blank of research and development of ocean-derived pan-apoptosis inhibitors, combining with the brand-new biological activity discovery of known sequence peptides, the ocean small molecule peptide which c