文献类型：期刊文献

英文题名：Blocking the PD-1 signal transduction by occupying the phosphorylated ITSM recognition site of SHP-2

作者：Li, Wenjie[1];Mei, Wenyi[1];Jiang, Hewei[2,11];Wang, Jie[1];Li, Xiaoli[3,4];Quan, Lina[1];Diao, Yanyan[1];Ma, Yanni[5];Fan, Sisi[1];Xie, Zhuwei[1];Gong, Mengdie[1];Zhu, Huan[1];Bi, Dewen[3,4];Zhang, Feng[6];Ma, Lei[1];Zhang, Jian[1];Gao, Yufeng[7];Paschalidis, Aris[8];Lin, Honghuang[8];Liu, Fangfang[9];Liu, Kangdong[9];Ye, Mingliang[5];Zhao, Zhenjiang[1];Duan, Yajun[6];Chen, Zhuo[1];Xu, Yufang[1];Xiao, Weilie[3,4];Tao, Shengce[2];Zhu, Lili[1];Li, Honglin[1,10,11]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Shanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Key Lab Syst Biomed, Minist Educ, Shanghai 200240, Peoples R China;[3]Yunnan Univ, Yunnan Prov Ctr Res & Dev Nat Prod, Sch Pharm, State Key Lab Conservat & Utilizat Bioresources Yu, Kunming 650500, Peoples R China;[4]Yunnan Univ, Sch Chem Sci & Technol, Kunming 650500, Peoples R China;[5]Chinese Acad Sci, Inst Chem Phys, Natl Chromatog R&A Ctr Dalian, CAS Key Lab Separat Sci Analyt Chem, Dalian 116023, Peoples R China;[6]Univ Sci & Technol China, Affiliated Hosp USTC 1, Dept Cardiol, Div Life Sci & Med, Hefei 230027, Peoples R China;[7]Anhui Med Univ, Affiliated Hosp 1, Dept Infect Dis, Hefei 230022, Peoples R China;[8]Univ Massachusetts Chan Med Sch, Dept Med, Worcester, MA 01655 USA;[9]Zhengzhou Univ, Acad Med Sci, Coll Med, Dept Pathophysiol,Sch Basic Med Sci, Zhengzhou 450001, Peoples R China;[10]East China Normal Univ, Innovat Ctr AI & Drug Discovery, Shanghai 200062, Peoples R China;[11]Lingang Lab, Shanghai 200031, Peoples R China

年份：2025

卷号：68

期号：1

起止页码：189

外文期刊名：SCIENCE CHINA-LIFE SCIENCES

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001306198600001)】；

基金：We thank Professor Yongjun Dang for providing the CHO-PD-L1-CD3L cell line and Jurkat-PD-1-NFAT cell line. This work was supported in part by the National Natural Science Foundation of China (81825020, 82150208, 82260682), the National Key R&D Program of China (2022YFC3400501, 2022YFC3400504), the Shanghai Science and Technology Commission Biomedical Science and Technology Support Special Project (21S11907900, 20S11901000) and Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform (2022YKZY001). Honglin Li is also sponsored by the National Program for Special Supports of Eminent Professionals and National Program for Support of Top-notch Young Professionals.

语种：英文

外文关键词：pygenic acid A; programmed death-1; immunoreceptor tyrosine-based switch motif; SH2 domain-containing protein-tyrosine phosphatase-2; target identification; site recognition

摘要：Targeting the PD-1/PD-L1 axis with small-molecular inhibitors is a promising approach for immunotherapy. Here, we identify a natural pentacyclic triterpenoid, Pygenic Acid A (PA), as a PD-1 signaling inhibitor. PA exerts anti-tumor activity in hPD-1 knock-in C57BL/6 mice and enhances effector functions of T cells to promote immune responses by disrupting the PD-1 signaling transduction. Furthermore, we identify SHP-2 as the direct molecular target of PA for inhibiting the PD-1 signaling transduction. Subsequently, mechanistic studies suggest that PA binds to a new druggable site in the phosphorylated PD-1 ITSM recognition site of SHP-2, inhibiting the recruitment of SHP-2 by PD-1. Taken together, our findings demonstrate that PA has a potential application in cancer immunotherapy and occupying the phosphorylated ITSM recognition site of SHP-2 may serve as an alternative strategy to develop PD-1 signaling inhibitors. In addition, our success in target recognition provides a paradigm of target identification and confirmation for natural products.