| Literature DB >> 33510133 |
Shin-Ichiro Hattori1, Nobuyo Higashi-Kuwata1, Hironori Hayashi2,3, Srinivasa Rao Allu4, Jakka Raghavaiah4, Haydar Bulut5, Debananda Das5, Brandon J Anson6, Emma K Lendy6, Yuki Takamatsu1, Nobutoki Takamune7, Naoki Kishimoto8, Kazutaka Murayama9, Kazuya Hasegawa10, Mi Li11,12, David A Davis13, Eiichi N Kodama3,14, Robert Yarchoan13, Alexander Wlodawer11, Shogo Misumi8, Andrew D Mesecar6, Arun K Ghosh4, Hiroaki Mitsuya15,16,17.
Abstract
Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.Entities:
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Year: 2021 PMID： 33510133 PMCID： PMC7843602 DOI： 10.1038/s41467-021-20900-6
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919