Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry PMID: 37990007

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2023 Nov 21;14(1):7574. doi: 10.1038/s41467-023-42527-5.

Haofeng Wang ^# ¹ ² , Qi Yang ^# ³ , Xiaoce Liu ^# ¹ ² , Zili Xu ^# ⁴ ⁵ , Maolin Shao ^# ¹ ² , Dongxu Li ¹ ² , Yinkai Duan ¹ ² , Jielin Tang ³ , Xianqiang Yu ¹ ⁵ , Yumin Zhang ⁶ , Aihua Hao ⁷ , Yajie Wang ⁷ , Jie Chen ¹ ² , Chenghao Zhu ¹ , Luke Guddat ⁸ , Hongli Chen ¹ ⁵ , Leike Zhang ⁹ , Xinwen Chen ¹⁰ , Biao Jiang ¹¹ ¹² , Lei Sun ¹³ , Zihe Rao ¹ ² ³ ¹⁴ ¹⁵ ¹⁶ , Haitao Yang ¹⁷ ¹⁸

Affiliations

1. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
2. Shanghai Clinical Research and Trial Center, Shanghai, P.R. China.
3. Guangzhou Laboratory, Guangzhou, China.
4. School of Physical Science and Technology, ShanghaiTech University, Shanghai, China.
5. University of Chinese Academy of Sciences, Beijing, China.
6. CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
7. The Fifth People's Hospital of Shanghai, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
8. School of Chemistry and Molecular Biosciences, the University of Queensland, Brisbane, Queensland, Australia.
9. CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China. [email protected].
10. Guangzhou Laboratory, Guangzhou, China. [email protected].
11. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
12. University of Chinese Academy of Sciences, Beijing, China. [email protected].
13. The Fifth People's Hospital of Shanghai, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].
14. Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China.
15. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and College of Pharmacy, Nankai University, Tianjin, China.
16. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
17. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
18. Shanghai Clinical Research and Trial Center, Shanghai, P.R. China. [email protected].
# Contributed equally.

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.