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- Title
Discovery of the covalent SARS‐CoV‐2 M<sup>pro</sup> inhibitors from antiviral herbs via integrating target‐based high‐throughput screening and chemoproteomic approaches.
- Authors
Zhang, Ya‐Ni; Zhu, Guang‐Hao; Liu, Wei; Chen, Xi‐Xiang; Xie, Yuan‐Yuan; Xu, Jian‐Rong; Jiang, Mei‐Fang; Zhuang, Xiao‐Yu; Zhang, Wei‐Dong; Chen, Hong‐Zhuan; Ge, Guang‐Bo
- Abstract
The main proteases (Mpro) are highly conserved cysteine‐rich proteins that can be covalently modified by numerous natural and synthetic compounds. Herein, we constructed an integrative approach to efficiently discover covalent inhibitors of Mpro from complex herbal matrices. This work begins with biological screening of 60 clinically used antiviral herbal medicines, among which Lonicera japonica Flos (LJF) demonstrated the strongest anti‐Mpro effect (IC50 = 37.82 μg/mL). Mass spectrometry (MS)‐based chemical analysis and chemoproteomic profiling revealed that LJF extract contains at least 50 constituents, of which 22 exhibited the capability to covalently modify Mpro. We subsequently verified the anti‐Mpro effects of these covalent binders. Gallic acid and quercetin were found to potently inhibit severe acute respiratory syndrome coronavirus 2 Mpro in dose‐ and time‐ dependent manners, with the IC50 values below 10 µM. The inactivation kinetics, binding affinity and binding mode of gallic acid and quercetin were further characterized by fluorescence resonance energy transfer, surface plasmon resonance, and covalent docking simulations. Overall, this study established a practical approach for efficiently discovering the covalent inhibitors of Mpro from herbal medicines by integrating target‐based high‐throughput screening and MS‐based assays, which would greatly facilitate the discovery of key antiviral constituents from medicinal plants.
- Subjects
SARS-CoV-2; HIGH throughput screening (Drug development); FLUORESCENCE resonance energy transfer; QUERCETIN; JAPANESE honeysuckle; SURFACE plasmon resonance
- Publication
Journal of Medical Virology, 2023, Vol 95, Issue 11, p1
- ISSN
0146-6615
- Publication type
Article
- DOI
10.1002/jmv.29208