期刊
VIRUSES-BASEL
卷 13, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/v13020174
关键词
SARS-CoV-2; Covid-19; main protease; M-pro; ML188; protease inhibitor; crystal structure; structure-based drug design; direct-acting antivirals
类别
资金
- National Institute of General Medical Sciences [R01 GM135919, R35 GM118112]
- National Institute of Allergy and Infectious Diseases [R21 AI149716]
Viral proteases are crucial enzymes for the maturation of human pathogenic viruses, and ML188, a non-covalent inhibitor, shows more potency against SARS-CoV-2 M-pro. These non-covalent inhibitors play a critical role in the design of DAAs for treating COVID-19.
Viral proteases are critical enzymes for the maturation of many human pathogenic viruses and thus are key targets for direct acting antivirals (DAAs). The current viral pandemic caused by SARS-CoV-2 is in dire need of DAAs. The Main protease (M-pro) is the focus of extensive structure-based drug design efforts which are mostly covalent inhibitors targeting the catalytic cysteine. ML188 is a non-covalent inhibitor designed to target SARS-CoV-1 M-pro, and provides an initial scaffold for the creation of effective pan-coronavirus inhibitors. In the current study, we found that ML188 inhibits SARS-CoV-2 M-pro at 2.5 mu M, which is more potent than against SAR-CoV-1 M-pro. We determined the crystal structure of ML188 in complex with SARS-CoV-2 M-pro to 2.39 angstrom resolution. Sharing 96% sequence identity, structural comparison of the two complexes only shows subtle differences. Non-covalent protease inhibitors complement the design of covalent inhibitors against SARS-CoV-2 main protease and are critical initial steps in the design of DAAs to treat CoVID 19.
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