7L0D

Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188.

(2021) Viruses 13

• PubMed: 33503819 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.3390/v13020174
• Primary Citation of Related Structures:  
  7L0D


• PubMed 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 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 ?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 ? 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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Organizational Affiliation: 

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.