1. Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188.
- Author
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Lockbaum GJ, Reyes AC, Lee JM, Tilvawala R, Nalivaika EA, Ali A, Kurt Yilmaz N, Thompson PR, and Schiffer CA
- Subjects
- Amino Acid Sequence, Antiviral Agents metabolism, Catalytic Domain, Coronavirus 3C Proteases antagonists & inhibitors, Coronavirus 3C Proteases metabolism, Crystallography, X-Ray, Drug Discovery, Inhibitory Concentration 50, Models, Molecular, Protease Inhibitors metabolism, Protein Binding, Severe acute respiratory syndrome-related coronavirus enzymology, Antiviral Agents chemistry, Coronavirus 3C Proteases chemistry, Protease Inhibitors chemistry, SARS-CoV-2 enzymology
- Abstract
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 Mpro , 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 Mpro at 2.5 µM, which is more potent than against SAR-CoV-1 Mpro . We determined the crystal structure of ML188 in complex with SARS-CoV-2 Mpro to 2.39 Å 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.- Published
- 2021
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