Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry

Haofeng Wang, Qi Yang, Xiaoce Liu, Zili Xu, Maolin Shao, Dongxu Li, Yinkai Duan, Jielin Tang, Xianqiang Yu, Yumin Zhang, Aihua Hao, Yajie Wang, Jie Chen, Chenghao Zhu, Luke Guddat, Hongli Chen, Leike Zhang (), Xinwen Chen (), Biao Jiang (), Lei Sun (), Zihe Rao and Haitao Yang ()
Additional contact information
Haofeng Wang: ShanghaiTech University
Qi Yang: Guangzhou Laboratory
Xiaoce Liu: ShanghaiTech University
Zili Xu: ShanghaiTech University
Maolin Shao: ShanghaiTech University
Dongxu Li: ShanghaiTech University
Yinkai Duan: ShanghaiTech University
Jielin Tang: Guangzhou Laboratory
Xianqiang Yu: ShanghaiTech University
Yumin Zhang: Chinese Academy of Sciences
Aihua Hao: Fudan University
Yajie Wang: Fudan University
Jie Chen: ShanghaiTech University
Chenghao Zhu: ShanghaiTech University
Luke Guddat: the University of Queensland
Hongli Chen: ShanghaiTech University
Leike Zhang: Chinese Academy of Sciences
Xinwen Chen: Guangzhou Laboratory
Biao Jiang: ShanghaiTech University
Lei Sun: Fudan University
Zihe Rao: ShanghaiTech University
Haitao Yang: ShanghaiTech University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants of concern. Host proteases, TMPRSS2 and CTSL/CTSB cleave the SARS-CoV-2 spike to play a crucial role in the two alternative pathways of viral entry and are characterized as promising pharmacological targets. Here, we identify compounds that show potent inhibition of these proteases and determine their complex structures with their respective targets. Furthermore, we show that applying inhibitors simultaneously that block both entry pathways has a synergistic antiviral effect. Notably, we devise a bispecific compound, 212-148, exhibiting the dual-inhibition ability of both TMPRSS2 and CTSL/CTSB, and demonstrate antiviral activity against various SARS-CoV-2 variants with different viral entry profiles. Our findings offer an alternative approach for the discovery of SARS-CoV-2 antivirals, as well as application for broad-spectrum treatment of viral pathogenic infections with similar entry pathways.

Date: 2023
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DOI: 10.1038/s41467-023-42527-5

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