Identification and optimization of peptide inhibitors to block VISTA/PSGL-1 interaction for cancer immunotherapy  

作　　者：Xiaoshuang Niu Menghan Wu Guodong Li Xiuman Zhou Wenpeng Cao Wenjie Zhai Aijun Wu Xiaowen Zhou Shengzhe Jin Guanyu Chen Yanying Li Jiangfeng Du Yahong Wu Lu Qiu Wenshan Zhao Yanfeng Gao 

机构地区：[1]School of Life Sciences,Zhengzhou University,Zhengzhou 450001,China [2]School of Pharmaceutical Sciences(Shenzhen),Shenzhen Campus of Sun Yat-sen University,Shenzhen 518107,China [3]International Joint Laboratory for Protein and Peptide Drugs of Henan Province,Zhengzhou University,Zhengzhou 450001,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第11期4511-4522,共12页药学学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China (U1904147,U20A20369);Shenzhen Science and Technology Program (KQTD20190929173853397,China);“Pearl River Talent Plan”Innovation and Entrepreneurship Team Project of Guangdong Province (2019ZT08Y464,China)。

摘　　要：Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer patients.Here,we discovered that the novel immune checkpoint VISTA is highly expressed on a variety of tumor-infiltrating immune cells,especially myeloid derived suppressor cells(MDSCs)and CD8^(+)T cells.Then,peptide C1 with binding affinity to VISTA was developed by phage displayed bio-panning technique,and its mutant peptide VS3 was obtained by molecular docking based mutation.Peptide VS3 could bind VISTA with high affinity and block its interaction with ligand PSGL-1 under acidic condition,and elicit anti-tumor activity in vivo.The peptide DVS3-Pal was further designed by D-amino acid substitution and fatty acid modification,which exhibited strong proteolytic stability and significant anti-tumor activity through enhancing CD8^(+)T cell function and decreasing MDSCs infiltration.This is the first study to develop peptides to block VISTA/PSGL-1 interaction,which could act as promising candidates for cancer immunotherapy.

关 键 词：Immune checkpoint VISTA PSGL-1 Phage displayed biopanning PEPTIDE Cancer immunotherapy MDSC T cell 

分 类 号：TP3[自动化与计算机技术—计算机科学与技术]