TitleDesign of Dimeric Bile Acid Derivatives as Potent and Selective Human NTCP Inhibitors
AuthorsLiu, Yang
Zhang, Lei
Yan, Huan
Wang, Zhiqiang
Sun, Guoliang
Song, Xiao
Zhou, Zhongmin
Peng, Bo
Yan, Liwei
Wu, Qingcui
Li, Wenhui
Qi, Xiangbing
AffiliationNatl Inst Biol Sci, Beijing 102206, Peoples R China
Tsinghua Univ, Grad Program, Beijing 100084, Peoples R China
Beijing Normal Univ, Coll Life Sci, Beijing 100875, Peoples R China
Peking Univ, Grad Program, Beijing 100080, Peoples R China
Tsinghua Univ, Tsinghua Inst Multidisciplinary Biomed Res, Beijing 100084, Peoples R China
KeywordsB-VIRUS ENTRY
HEPATITIS-B
CYCLOSPORINE-A
HUMAN SERUM
TRANSPORTER
CLONING
Issue Date13-May-2021
PublisherJOURNAL OF MEDICINAL CHEMISTRY
AbstractDimeric bile acid derivatives (DBADs) were developed and tested for their anti-HBV and anti-HDV activities as sodium taurocholate cotransporting polypeptide (NTCP) inhibitors. DBADs exhibited strong and persistent potency of NTCP inhibition, whereas diverse linkers and constitutions showed distinct inhibition features. Motif aa157-165 on NTCP was shown to be a possible binding site of DBADs; therefore, we determined DBADs' selectivity among NTCPs from different species. A cyclized DBAD scaffold DBA-41 exhibited a high affinity to human NTCP (hNTCP). Intraperitoneal administration of DBA-41 to hNTCP-tg mice induced serum total bile acid elevation. DBA-41 may serve as a biological tool to study NTCP physiological function.
URIhttp://hdl.handle.net/20.500.11897/614210
ISSN0022-2623
DOI10.1021/acs.jmedchem.1c00078
IndexedSCI(E)
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