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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Nat+Commun 2021 ; 12 (1): 668 Nephropedia Template TP
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A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication #MMPMID33510133
Hattori SI; Higashi-Kuwata N; Hayashi H; Allu SR; Raghavaiah J; Bulut H; Das D; Anson BJ; Lendy EK; Takamatsu Y; Takamune N; Kishimoto N; Murayama K; Hasegawa K; Li M; Davis DA; Kodama EN; Yarchoan R; Wlodawer A; Misumi S; Mesecar AD; Ghosh AK; Mitsuya H
Nat Commun 2021[Jan]; 12 (1): 668 PMID33510133show ga
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 (M(pro)). 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 EC(50) values of 15 +/- 4 and 4.2 +/- 0.7 muM 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 M(pro) and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead M(pro) inhibitor for the development of therapeutics for SARS-CoV-2 infection.