Discovery Of A Novel Sodium Taurocholate Cotransporting Polypeptide (Ntcp) Inhibitor: Design, Synthesis, And Anti-Proliferative Activities

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. (C) 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.