CN-122011059-A - Development and application of novel glycolipid Toll-like Receptor 2 agonist

Abstract

The invention belongs to the fields of pharmaceutical chemistry and pharmacology, and relates to application of a novel glycolipid TLR2 agonist 13-C in vaccine adjuvant preparation and anti-tumor treatment. The compound has excellent humanized TLR2 agonistic activity, EC50 of 2.2 nM, simple structure, easy preparation, excellent solubility and industrialization application potential. In the B16-OVA tumor model, the antibody induction capacity is better than that of a positive control drug Diprovocim, the anti-tumor activity is more obvious, the expression of PD-L1 in tumor tissues can be effectively reduced, and a synergistic anti-tumor effect is generated with PD-L1 monoclonal antibody Atezolizumab. In addition, the combination of 13-C and vaccine adjuvant QS-21 has synergistic enhancement effect, can obviously improve the antibody titer induced by vaccine and enrich antibody subtype, and simultaneously excite cellular immunity and humoral immunity response of organism, thus realizing the effect of double immune activation.

Inventors

• WANG XIAOLEI
• JIA HONGBIN
• MA WEI
• LUO ZHIKUAN

Assignees

• 兰州大学

Dates

Publication Date

20260512

Application Date

20260128

Claims (7)

1. 1. A novel glycolipid compound, and pharmaceutically acceptable salts, isotopes and isomers thereof, having a structure represented by formula I: Wherein R 1 is CO (CH 2 )nCH 3 ,R 2 is hydrogen, CO (CH 2 )mCH 3 ,R 3 is CO (CH 2 )mCH 3 , X is O or S, Y is O or NH, n and m are fatty chains of 8-18 methylene groups respectively).
2. 2. The compound of claim 1, wherein X is O or S, Y is O or NH, and when X is S, Y is not NH.
3. 3. A compound according to claim 2, wherein the sum compound is selected from the following structures: 。
4. 4. A pharmaceutical composition comprising the novel glycolipid compound of any one of claims 1 to 3 and a pharmaceutically acceptable carrier or diluent thereof.
5. 5. Use of a novel glycolipid compound according to any one of claims 1 to 3 and pharmaceutically acceptable compositions thereof for the manufacture of a medicament capable of activating TLR2 receptors and activating signal pathways mediated thereby.
6. 6. The use according to claim 5, wherein the medicament is used alone or in combination with other agents, in vaccine adjuvants, in tumor immunotherapy and in modulating immunity.
7. 7. A compound according to any one of claims 1 to 3, or a composition thereof, for use in combination with other drugs, preferably PD-L1 and PD1 antibodies.

Description

Development and application of novel glycolipid Toll-like Receptor 2 agonist Technical Field The invention relates to the technical fields of pharmaceutical chemistry and pharmacology, in particular to application of a novel glycolipid Toll-like Receptor 2 agonist in vaccine adjuvants and tumor immunotherapy. Background Vaccines play an important role in preventing and controlling infectious diseases, anti-tumor and the like, but the lack of suitable adjuvants has been a bottleneck in developing novel vaccines. The adjuvant can not only enhance the immune response of the antibody, but also enhance the intensity and the specificity of the immune response of the vaccine antigen mediated by B lymphocytes and T lymphocytes. In addition, adjuvants can also overcome competition between antigens in combination vaccines, thereby enhancing the immune response in young children and the elderly. However, to date, only a few adjuvants have been used in batches due to significant regulatory hurdles. Small molecules or biological macromolecules synthesized by targeting Pattern Recognition Receptors (PRRs) are next-generation vaccine adjuvants, belonging to immunopotentiators. Recent evidence suggests that PRRs recognize not only pathogen-associated molecular patterns (PAMPs), but also endogenous molecules released by damaged cells (DAMPs). Since the discovery of these innate immune receptors responsible for detecting PAMPs and activating downstream signals, the field of vaccine adjuvant development has revolutionized. Several ligands for different PRRs have been identified as vaccine adjuvants. However, each PRRs has its own specific tissue localization and downstream gene signaling pathways, which provides an opportunity to tailor adjuvants with the desired properties. TLRs (Toll-like receptors) are the most characteristic of the PRRs family and are responsible for sensing the invading pathogens in extracellular and intracellular endosomes and lysosomes. Different TLRs recognize different microbial molecules and self-components. Each TLR has its own specific tissue localization and downstream signaling pathway. Wherein TLR2 is expressed on a variety of cell surfaces including monocytes, macrophages, endothelial cells, epithelial cells, natural killer cells, dendritic cells, bone marrow suppressive cells, platelets, mast cells and the like. It can detect bacterial, mycoplasma, fungal and viral components, including bacterial and mycoplasma lipoproteins, etc. Meanwhile, since TLR2 is capable of forming heterodimers with TLR1 and TLR6 on the cell surface, its library of recognition pathogen-associated molecular patterns (PAMPs) is very broad. TLRs agonists are often used as immunotherapeutic or vaccine adjuvants for the treatment of cancer, allergies and infectious diseases. Some TLR agonists are currently in clinical trials or have been approved by the FDA. For example, the TLR2 and TLR4 agonists BCG are used to prevent tuberculosis and to treat bladder cancer, the TLR4 agonist monophosphorylated lipid a is used as an adjuvant to hepatitis b vaccine Fendrix and HPV-associated cervical cancer vaccine Cervarix, the TLR5 agonist antolimo has been used to treat tumors, infections and digestive system diseases, and the TLR7 agonist imiquimod has been widely used to treat malignant skin cancer. Unlike other members of the TLR family, TLR2 can form heterodimers with TLR1 or TLR6, enabling the structure of TLR2 agonists to be more diverse. These promising potential applications motivate us to explore and discover new TLR2 agonists. Team Clardy found a lipid-type small molecule agonist CaLGL-1 of moderate molecular weight from Collinsella aerofaciens. CaLGL-1 was further demonstrated by knockout experiments to be a TLR 2-dependent agonist (EC 50 =3.2 μm) in mouse bone marrow derived dendritic cells (BMDCs). Although CaLGL-1 has poor agonist activity on human TLR2, it still provides a promising lead compound for developing an effective TLR2 receptor agonist specific to human. CalGL-1 of the formula: The invention aims to develop a novel glycolipid Toll-like Receptor 2 agonist which is applied to vaccine adjuvants and anti-tumor, and provides a new idea for subsequent study of TLR-2 agonists and related drugs. Disclosure of Invention The invention discloses application of a novel glycolipid Toll-like Receptor 2 agonist in vaccine adjuvants and anti-tumor. The invention aims to provide a novel glycolipid Toll-like Receptor 2 compound, which has a specific structural formula shown in the following (I): Wherein R 1 is CO (CH 2)nCH3,R2 is hydrogen, CO (CH 2)mCH3,R3 is CO (CH 2)mCH3, X is a heteroatom such as oxygen and sulfur, Y is a heteroatom such as oxygen and nitrogen, and n and m are fatty chains of 8-18 methylene groups, respectively; specifically, X is O or S, Y is O or NH, n and m are fatty chains of 8-18 methylene groups, preferably, X is O or S, Y is O or NH, and when X is S, Y is not NH, n and m are fatty chains of 8-18 methy