首页|Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1
Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1
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Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxi-dation 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)po-tency and blocked the viral entry stage through a host mechanism of action.Using chemoproteomic tech-niques,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 antivi-ral candidates against human β-coronavirus,including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).
Beijing Key Laboratory of Antimicrobial Agents,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China
Department of Pharmacy,Affiliated Hospital of Jining Medical University,Jining Medical University,Jining 272000,China
国家自然科学基金Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences
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