Xiangbing Qi/Wenhui Li labs developed highly active dimeric bile acids NTCP inhibitor

April 28, 2021, Xiangbing Qi and Wenhui Li labs at NIBS/ Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University have published “Design of Dimeric Bile Acid Derivatives as Potent and Selective Human NTCP Inhibitors” paper in《J. Med. Chem.》 (https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.1c00078)。

Hepatitis B virus (HBV) infection remains a global public health problem. A global prevalence study indicated that about 290 million people are chronically infected. This chronic infection often leads to the development of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis D virus (HDV) is a satellite viroid that hijacks HBV envelope proteins for viral assembly, and thus shares similar early entry mechanism with HBV. Sodium taurocholate cotransporting polypeptide (NTCP, encoded by the SLC10A1 gene) was identified to be a functional receptor for the entry of HBV and HDV into hepatocytes. It is a membrane protein predominantly expressed on the sinusoidal membrane of hepatocytes, contributing to the majority of the hepatic uptake of bile acids, sulfated steroids hormones, sulfated thyroidal hormones, and various drugs. NTCP mRNA expression is low in human hepatocarcinoma cell lines, thus HepG2 cells stably expressing human NTCP (HepG2-NTCP cells) offers a convenient and efficient HBV and HDV in vitro infection model.
Despite that modulating NTCP activity has pronounced potential for controlling HBV/HDV infection and the associated diseases, till to date, the only and first-in-class NTCP inhibitor that came to clinical research is Myrcludex B, which is a polypeptide derived from HBV Pre-S1 peptide. However, this compound is limited in intravenously or subcutaneously administration. In this study, we fortuitously discovered a series of dimeric bile acids (DBADs) as potent NTCP inhibitors, and therefore designed and synthesized dozens of dimeric bile acid derivatives. We then conducted thorough SAR studies and evaluated their anti-HBV activities on HepG2-NTCP cells. This bivalent drug design with distinctive structure features have also been demonstrated by different inhibition properties and species selectivities. Encouragingly, we found some DBADs exhibit strong and persistent inhibition potency with IC50 lower than 50 nM. In addition, we found motif aa157-165, a known motif for monkey specific host range of HBV Pre-S1 binding on NTCP, was involved in DBADs binding. Finally, we developed a highly potent, highly affinitive to human NTCP compound DBA-41 and investigated its in vivo efficacy in human NTCP knock-in mice.

Yang Liu and HuanYan, Ph.D. students at Li’s lab and Lei Zhang, a Ph.D. student and Zhiqiang Wang from Qi’s lab have made great contributions to this work. Other authors including, Qingcui Wu, Xiao Song, Guoliang Sun, Zhongmin Zhou, Bo Peng and Liwei Yan. The work was supported by Chinese Ministry of Science and Technology 973 grant, Beijing Municipal Science & Technology Commission, and Tsinghua University. This work was carried out at National Institute of Biological Sciences, Beijing.

Full text link：https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.1c00078