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A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication.
Hattori, Shin-Ichiro; Higashi-Kuwata, Nobuyo; Hayashi, Hironori; Allu, Srinivasa Rao; Raghavaiah, Jakka; Bulut, Haydar; Das, Debananda; Anson, Brandon J; Lendy, Emma K; Takamatsu, Yuki; Takamune, Nobutoki; Kishimoto, Naoki; Murayama, Kazutaka; Hasegawa, Kazuya; Li, Mi; Davis, David A; Kodama, Eiichi N; Yarchoan, Robert; Wlodawer, Alexander; Misumi, Shogo; Mesecar, Andrew D; Ghosh, Arun K; Mitsuya, Hiroaki.
  • Hattori SI; Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • Higashi-Kuwata N; Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • Hayashi H; Department of Intelligent Network for Infection Control, Tohoku University Hospital, Miyagi, Japan.
  • Allu SR; Department of infectious Diseases, International Research Institute of Disaster Science, Tohoku University, Miyagi, Japan.
  • Raghavaiah J; Department of Chemistry and Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
  • Bulut H; Department of Chemistry and Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
  • Das D; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Anson BJ; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Lendy EK; Department of Biochemistry and Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
  • Takamatsu Y; Department of Biochemistry and Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
  • Takamune N; Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • Kishimoto N; Kumamoto Innovative Development Organization, Kumamoto University, Kumamoto, Japan.
  • Murayama K; Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
  • Hasegawa K; Graduate School of Biomedical Engineering, Tohoku University, Miyagi, Japan.
  • Li M; Protein Crystal Analysis Division, Japan Synchrotron Radiation Research Institute, Hyogo, Japan.
  • Davis DA; Protein Structure Section, Center for Structural Biology, National Cancer Institute, Frederick, MD, USA.
  • Kodama EN; Basic Science Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Yarchoan R; Viral Oncology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Wlodawer A; Department of infectious Diseases, International Research Institute of Disaster Science, Tohoku University, Miyagi, Japan.
  • Misumi S; Department of Infectious Diseases, Graduate School of Medicine and Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan.
  • Mesecar AD; Viral Oncology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Ghosh AK; Protein Structure Section, Center for Structural Biology, National Cancer Institute, Frederick, MD, USA.
  • Mitsuya H; Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Nat Commun ; 12(1): 668, 2021 01 28.
Article in English | MEDLINE | ID: covidwho-1387328
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Viral Proteases / Coronavirus Protease Inhibitors / SARS-CoV-2 / COVID-19 Drug Treatment Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-20900-6

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Viral Proteases / Coronavirus Protease Inhibitors / SARS-CoV-2 / COVID-19 Drug Treatment Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-20900-6