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 µM, 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 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.
【저자키워드】 COVID-19, SARS-CoV-2, main protease, Structure-based drug design, Protease inhibitor, MPro, crystal structure, Direct-acting antivirals, ML188, 【초록키워드】 pandemic, Antiviral, drug design, complement, protease, SARS-CoV-1, inhibitors, SARS-CoV-2 main protease, target, inhibitor, Critical, cysteine, maturation, enzyme, complex, M pro, effort, treat, sequence identity, effective, initial, caused, inhibit, provide, complexes, catalytic, pathogenic virus, acting, 【제목키워드】 Structure, crystal,