CN-122011128-A - Double-target inhibition polypeptide or pharmaceutically acceptable salt thereof and application thereof

Abstract

The application relates to the technical field of biological pharmacy, and provides a double-target inhibition polypeptide or pharmaceutically acceptable salt thereof and application thereof, wherein the polypeptide comprises an amino acid sequence TASPILYQMCCDYKR, and an amino acid fragment with a structure shown in a formula (I) is connected to the C end of the sequence, namely X 1 WGIX 2 HSHFTHTX 3 WKX 4 (I). The polypeptide or the pharmaceutically acceptable salt thereof can simultaneously generate high-affinity binding with PD-1 and CTLA-4, has excellent biological blocking activity, can obviously improve the proportion of effector T cell subsets in tumor tissues, and effectively enhances the anti-tumor immune response of organisms. Therefore, the polypeptide or the pharmaceutically acceptable salt thereof can be used for the related detection of PD-1 and CTLA-4, can be used as a novel antitumor candidate drug, and provides a brand-new treatment scheme for cancer patients.

Inventors

• HE BING
• Lv Tianxu
• YAO JIANHUA

Assignees

• 腾讯科技（深圳）有限公司

Dates

Publication Date

20260512

Application Date

20260414

Claims (11)

1. 1. A polypeptide or a pharmaceutically acceptable salt thereof, which is characterized in that the amino acid sequence of the polypeptide is shown as SEQ ID NO. 1 or SEQ ID NO. 2.
2. 2. A polypeptide derivative or a pharmaceutically acceptable salt thereof, comprising: the polypeptide of claim 1, or a pharmaceutically acceptable salt thereof, and A modifying group, said polypeptide or a pharmaceutically acceptable salt thereof being linked to said modifying group.
3. 3. The polypeptide derivative or pharmaceutically acceptable salt thereof according to claim 2, wherein the modifying group is attached to-NH 2 , -SH, -OH or-COOH of the amino acid side chain in the polypeptide.
4. 4. A polypeptide derivative or a pharmaceutically acceptable salt thereof according to claim 3, wherein the modifying group is attached to-NH 2 of an amino acid side chain in the polypeptide; The modifying group has at least one of the following structures: ; ; ; 。
5. 5. A fusion protein comprising the polypeptide of claim 1 or a pharmaceutically acceptable salt thereof, or the polypeptide derivative of any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof.
6. 6. A reagent or kit comprising the polypeptide of claim 1 or a pharmaceutically acceptable salt thereof, the polypeptide derivative of any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof, or the fusion protein of claim 5.
7. 7. A pharmaceutical composition comprising the polypeptide of claim 1 or a pharmaceutically acceptable salt thereof, the polypeptide derivative of any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof, or the fusion protein of claim 5.
8. 8. Use of the polypeptide of claim 1 or a pharmaceutically acceptable salt thereof, the polypeptide derivative of any one of claims 2-4 or a pharmaceutically acceptable salt thereof, the fusion protein of claim 5, or the pharmaceutical composition of claim 7 in the manufacture of a medicament which is an inhibitor of both PD-1 and CTLA-4 targets.
9. 9. Use of the polypeptide of claim 1 or a pharmaceutically acceptable salt thereof, the polypeptide derivative of any one of claims 2-4 or a pharmaceutically acceptable salt thereof, the fusion protein of claim 5, or the pharmaceutical composition of claim 7 in the manufacture of a medicament for treating or preventing a PD-1 and/or CTLA-4 related disease, inhibiting PD-1 and/or CTLA-4 activity, and/or promoting T cell proliferation.
10. 10. The use according to claim 9, wherein the PD-1 and/or CTLA-4 associated disease comprises cancer.
11. 11. A method of detecting PD-1 and/or CTLA-4, comprising: Contacting a sample to be tested with the polypeptide or a pharmaceutically acceptable salt thereof according to claim 1, the polypeptide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 4, the fusion protein according to claim 5, or the reagent or kit according to claim 6; Determining whether the sample to be detected contains PD-1 and/or CTLA-4 based on the signal generated by the contact product.

Description

Double-target inhibition polypeptide or pharmaceutically acceptable salt thereof and application thereof Technical Field The application belongs to the technical field of biological pharmacy, and particularly relates to a double-target inhibition polypeptide or pharmaceutically acceptable salt thereof and application thereof. Background In the field of tumor immunotherapy, programmed death receptor-1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are two most critical immune checkpoint proteins, both of which are involved in tumor immune escape regulation, but have significant differences in action phase and molecular mechanism. Wherein, PD-1 is mainly expressed on the surface of activated T cells, and after being combined with ligand (PD-L1/PD-L2) expressed on the surface of tumor cells, the PD-1 can transmit inhibitory signals to the T cells, so that the T cells are exhausted in function and further mediate the tumor cells to realize immune escape, while CTLA-4 mainly plays a role in the early stage of immune response (in lymph nodes), and limits the initial activation and proliferation of the T cells by competing with CD28 for binding with B7 ligand, thereby indirectly weakening the recognition capability of an immune system on the tumor cells. However, the current research and development focus on single-target antagonistic peptides against PD-1 or CTLA-4, and the core action mechanism is to block the interaction between the single-target antagonistic peptide and the corresponding ligand through high-specificity binding to PD-1 or CTLA-4, so that the inhibition effect on T cells is relieved, and the recognition and killing functions of an immune system on tumor cells are recovered. However, the tumor immune escape mechanism has high complexity and compensation, and when the PD-1 pathway is singly blocked, the tumor cells tend to realize the compensation escape by activating other immune check point pathways such as CTLA-4 and the like. Under the influence, the existing single-target polypeptide is difficult to generate enough immunity excitation strength due to single action mechanism, and cannot achieve the expected anti-tumor treatment effect. More importantly, in the field of polypeptide drugs, the research on dual-target peptides capable of simultaneously and precisely combining and blocking two targets of PD-1 and CTLA-4 is extremely deficient at present. The design of the double-target molecule has extremely high requirements on space configuration precision and screening technology, and the prior art is difficult to simultaneously consider the binding affinity of two targets and the stability of the molecule. Therefore, a novel double-target inhibitor targeting PD-1 and CTLA-4 is developed, and has important clinical value and application prospect for treating cancers and other related diseases. Disclosure of Invention The present application aims to solve at least one of the technical problems existing in the prior art to at least some extent. Therefore, the application provides a PD-1 and CTLA-4 double-target antagonistic polypeptide, which aims to solve the technical bottleneck that the existing single-target polypeptide has single effect, and the traditional PD-1 or CTLA-4 inhibitor is difficult to consider double-target binding efficiency and bioactivity, and provides a new efficient and targeted scheme for cancer treatment. According to the application, through combination of accurate molecular simulation calculation and deep learning model iterative optimization, the PD-1 and CTLA-4 double-target antagonistic polypeptide with a brand new structure is obtained by design. Compared with the traditional PD-1 and CTLA-4 inhibitors, the polypeptide has unique and optimized amino acid sequence arrangement, breaks through the limitation that double-target molecules in the prior art are difficult to consider target binding specificity and molecular stability, can simultaneously and specifically bind to PD-1 and CTLA-4, effectively block interaction between the PD-1 and the CTLA-4 and inhibit the PD-1/CTLA-4 mediated immunosuppression signal path. In addition, the double-target antagonistic polypeptide provided by the application has excellent binding affinity and biological activity to PD-1 and CTLA-4, and compared with the traditional single-target inhibitor or single antagonistic peptide, the double-target antagonistic polypeptide can effectively relieve T cell immunosuppression, effectively activate proliferation and killing functions of T cells, block tumor immune escape from double ways, further promote anti-tumor treatment effect, and provide a brand new treatment option with clinical application potential for cancer patients. Thus, in a first aspect of the application, the application provides a polypeptide or a pharmaceutically acceptable salt thereof. According to an embodiment of the application, the polypeptide comprises an amino acid sequence TASPILYQMCCDYKR, and an ami