Citation: Yulong Shi, Fenbei Chen, Mengyuan Wu, Xin Zhang, Runze Meng, Kun Wang, Yan Wang, Yuheng Mei, Qionglu Duan, Yinghong Li, Rongmei Gao, Yuhuan Li, Hongbin Deng, Jiandong Jiang, Yanxiang Wang, Danqing Song. Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1[J]. Chinese Chemical Letters, ;2024, 35(5): 108792. doi: 10.1016/j.cclet.2023.108792 shu

Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1

Yulong Shi ^{a, 1} ,
Fenbei Chen ^{a, 1} ,
Mengyuan Wu ^a ,
Xin Zhang ^b ,
Runze Meng ^a ,
Kun Wang ^a ,
Yan Wang ^a ,
Yuheng Mei ^a ,
Qionglu Duan ^a ,
Yinghong Li ^a ,
Rongmei Gao ^a ,
Yuhuan Li ^a ,
Hongbin Deng ^a ,
Jiandong Jiang ^a ,
Yanxiang Wang ^{a, *,} ,
Danqing Song ^{a, *,}

a.
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
b.
Department of Pharmacy, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining 272000, China

wangyanxiang@imb.pumc.edu.cn

songdanqing@imb.pumc.edu.cn

Received Date: 10 January 2023
Revised Date: 4 July 2023
Accepted Date: 6 July 2023
Available Online: 8 July 2023

Figures(5)

Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation 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) potency and blocked the viral entry stage through a host mechanism of action. Using chemoproteomic techniques, 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 antiviral candidates against human β-coronavirus, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
- Aloperine,
- SARS-CoV-2,
- TMPRSS2,
- SR-B1,
- Synthesis
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