Latest research: target peptide is expected to become tumor immunotherapy drug after optimization release time: April 12, 2019 reading capacity: 12043 source: this site

Beijing, Shanghai, March 26 (Ye Jiaqi, yuan Huiyun) recently, Xu Jie's research group of digestive Institute of Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine published in the Journal of nature biological engineering, entitled inhibiting programmed death ligand 1 (PD-L1) palmitoylation promoting T-cell antitumor immunity Against tumours). This paper reported the mechanism of palmitoylation of PD-L1 to promote its expression. Through the design of pd-palm polypeptide, the expression of PD-L1 in tumor cells was reduced, and the target polypeptide molecule which can competitively inhibit the palmitoylation of PD-L1 was developed, which provides a new way for the development of immunosuppressant. The target polypeptide molecule is expected to become a tumor immunotherapy drug after optimization.

While the paper was published online, the journal published a review by Professor Stephane lefrancois, a senior expert in the field of cell biology, explaining the scientific findings and significance of this work in detail. It is believed that "the use of peptide inhibitors to block PD-L1 palmitoylation suggests a new targeting method based on post-translational modification. The use of a peptide inhibitor to block the membrane deployment of PD-L1 highlights the potential of silent this post translational modification for therapeutic purposes to efficient PD-L1 suppression and could potentially be used as a therapeutic agent。 )

Immune checkpoints are inhibitory signaling pathways distributed in the body's immune system, which can regulate the strength and duration of immune response, avoid tissue damage and maintain the body's own tolerance. Tumor can evade the recognition of immune cells, especially the immune response of T cells by using the inhibition of immune checkpoint pathway. Therefore, inhibition of immune checkpoint can stimulate the original anti-tumor ability of the immune system. Monoclonal antibodies targeting immunocheckpoint proteins CTLA-4 and PD-1 / PD-L1 have been approved for the treatment of various types of malignant tumors.

However, there are still some problems in immunocheckpoint blocking therapy, such as low overall efficiency, drug resistance after long-term use and serious side effects. PD-L1 is the main ligand of PD-1. Some tumors rely on its expressed PD-L1 to bind to PD-1 on t surface and cause T cell failure, which makes tumors escape the surveillance and killing effect of host immune system. Therefore, in-depth study of the regulatory mechanism of PD-L1 will help to improve the therapeutic effect. In recent years, it has been found that PD-L1 is not only expressed on the cell surface, but also on the Golgi body, circulating body and microbubbles in the cell; PD-L1 in the cell has cancer promoting function and can be transported to the cell surface again. Therefore, the target protein degradation strategy aimed to completely eliminate PD-L1 is concerned. Xu Jie's group recently discovered the lysosomal degradation mechanism of PD-L1, and designed pd-lyso to target degradation of PD-L1 (Nature Chemical Biology 2019) inspired by Hip1R protein regulation mode.

Xu Jie's team found that PD-L1 protein can be palmitoylated by dhhc3 enzyme, and reduce its ubiquitination and lysosomal degradation. The elucidation of this mechanism will bring enlightenment to the research and development of PD-L1 inhibitors. Due to the lack of selectivity of small palmitoylation inhibitors for dhhc enzyme, Xu Jie's research group has tried to design competitive palmitoylation inhibitors. Because the specificity of dhhc enzyme is determined by the substrate sequence, the adjacent sequence of PD-L1 modified site may be modified by dhhc3, thus reducing the endogenous PD-L1 modification. Theoretically, this competitive peptide has little effect on other dhhc members, so it may be more selective than 2-BP. Through a series of experiments, the author proved that the design idea of the competitive inhibitor is effective, and through the design of pd-pal polypeptide, the expression of PD-L1 in tumor cells is reduced. On this basis, pd-pal can be modified and modified in the future to further improve its activity and stability and enhance its potential.

In this study, the palmitoylation of PD-L1 was studied in detail. The exact pathway of palmitoylation affecting lysosomal degradation of PD-L1 was revealed. A polypeptide PD-L1 inhibitor targeting palmitoylation was designed, which will bring enlightenment to palmitoylation related mechanism and transformation research.

The corresponding author of the paper is researcher Xu Jie, the first author is Dr. Yao Han, and the co first author is Dr. Lanjiang, Dr. Li Chushu and Professor Shi hubing. The project has been supported by the national key research and development plan and a number of National Natural Science Funds.

Shengnuo bio PRODUCT

Best sales manager contact

About Shengnuo

Chengdu Shengnuo Biotechnology Co., Ltd. has "Chengdu polypeptide drug engineering technology research center" in Chengdu, mainly engaged in polypeptide, polypeptide drug and beauty peptide research. Our zero defect has passed the FDA certification, and now it has become the first-class professional peptide drug and product development, technology transfer, technical service and peptide drug industry in the scale production and export of China's parks.