Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1  

作　　者：Yulong Shi Fenbei Chen Mengyuan Wu Xin Zhang Runze Meng Kun Wang Yan Wang Yuheng Mei Qionglu Duan Yinghong Li Rongmei Gao Yuhuan Li Hongbin Deng Jiandong Jiang Yanxiang Wang Danqing Song 

机构地区：[1]Beijing Key Laboratory of Antimicrobial Agents,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China [2]Department of Pharmacy,Affiliated Hospital of Jining Medical University,Jining Medical University,Jining 272000,China

出　　处：《Chinese Chemical Letters》2024年第5期201-206,共6页中国化学快报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.81974494);CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-070).

摘　　要：Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalability.Of them,compound 6b displayed a moderate anti-human coronavirus OC43(HCoV-OC43)potency and blocked the viral entry stage through a host mechanism of action.Using chemoproteomic techniques,both transmembrane serine protease 2(TMPRSS2)and scavenger receptor class B type 1(SR-B1)proteins,which act as host cofactors of viral entry,were identified to be the direct targets of 6b against HCoV-OC43.Furthermore,6b may deactivate the TMPRSS2 by inducing a change in protein conformation,rather than binding to its catalytic center,thus suppressing the viral membrane fusion.Accordingly,our study provided key scientific data for the development of aloperine derivatives into a new class of antiviral candidates against humanβ-coronavirus,including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).

关 键 词：ALOPERINE SARS-CoV-2 TMPRSS2 SR-B1 Synthesis 

分 类 号：TQ460.1[化学工程—制药化工]