Discovery of a novel sodium taurocholate cotransporting polypeptide(NTCP) inhibitor: Design, synthesis, and anti-proliferative activities  

作　　者：Honggang Xiang Yanmei Chen Jifa Zhang jin Zhang Dabo Pan Bo Liu Liang Ouyang 

机构地区：[1]State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,Collaborative Innovation Center for Biotherapy,Chengdu 610041,China [2]Institute of Traditional Chinese Medicine&Natural Products,Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research,College of Pharmacy,Jinan University,Guangzhou 510632,China

出　　处：《Chinese Chemical Letters》2020年第6期1422-1426,F0003,共6页中国化学快报（英文版）

基　　金：supported by National Science and Technology Major Project of the Ministry of Science and Technology of China(No.2018ZX09735005);the National Natural Science Foundation of China(Nos.81922064,81874290,81673290,81803347 and 81903502);the Natural Science Foundation of Guangdong Province(No.2018A030313707);Post-Doctor Research Project,West China Hospital,Sichuan University(No.2019HXBH034)。

摘　　要：Sodium taurocholate cotransporting polypeptide(NTCP)is identified as the functional receptor for HBV entry,which is responsible for upregulated HBV transcription in the HBV life cycle.Besides,NTCP is also implicated in the progression of HBV-induced hepatocellular carcinoma(HCC).Thereby,NTCP-targeting entry inhibitors are proposed to suppress HBV infection and replication in HBV-induced hepatoma therapy.Herein,we integrated in silico screening and chemical synthesis to obtain a small-molecule NTCP inhibitor B7,which exhibited moderate anti-proliferative activities against HepG2 cells and anti-HBV activity in vitro.Additionally,CETSA assay,molecular docking,and MD simulation validated that B7 could bind to NTCP.Furthermore,western blot analysis demonstrated that B7 induced apoptosis with an increased expression of Bax and caspase 3 cleaving as well as a decreasing expression of Bcl-2 in HepG2 cells.Taken together,our study identified B7 as a novel NTCP inhibitor with anti-proliferation activities which might provide a new opportunity for HCC therapy.

关 键 词：Sodium taurocholate cotransporting POLYPEPTIDE (NTCP) Hepatocellular carcinoma(HCC) HBV infection NTCP inhibitor Apoptosis 

分 类 号：R914[医药卫生—药物化学] TQ460.1[医药卫生—药学]