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GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection.
Hattori, Shin-Ichiro; Higshi-Kuwata, Nobuyo; Raghavaiah, Jakka; Das, Debananda; Bulut, Haydar; Davis, David A; Takamatsu, Yuki; Matsuda, Kouki; Takamune, Nobutoki; Kishimoto, Naoki; Okamura, Tadashi; Misumi, Shogo; Yarchoan, Robert; Maeda, Kenji; Ghosh, Arun K; Mitsuya, Hiroaki.
  • Hattori SI; Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • Higshi-Kuwata N; Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • Raghavaiah J; Department of Chemistry, Purdue University, West Lafayette, Indiana, USA.
  • Das D; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA.
  • Bulut H; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Davis DA; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Takamatsu Y; Viral Oncology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Matsuda K; Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • 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.
  • Okamura T; Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Science, Kumamoto University, Kumamoto, Japan.
  • Misumi S; Department of Laboratory Animal Medicine, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • Yarchoan R; Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Science, Kumamoto University, Kumamoto, Japan.
  • Maeda K; Viral Oncology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Ghosh AK; Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • Mitsuya H; Department of Chemistry, Purdue University, West Lafayette, Indiana, USA.
mBio ; 11(4)2020 08 20.
Article in English | MEDLINE | ID: covidwho-724620
ABSTRACT
We assessed various newly generated compounds that target the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and various previously known compounds reportedly active against SARS-CoV-2, employing RNA quantitative PCR (RNA-qPCR), cytopathicity assays, and immunocytochemistry. Here, we show that two indole-chloropyridinyl-ester derivatives, GRL-0820 and GRL-0920, exerted potent activity against SARS-CoV-2 in cell-based assays performed using VeroE6 cells and TMPRSS2-overexpressing VeroE6 cells. While GRL-0820 and the nucleotide analog remdesivir blocked SARS-CoV-2 infection, viral breakthrough occurred. No significant anti-SARS-CoV-2 activity was found for several compounds reportedly active against SARS-CoV-2 such as lopinavir, nelfinavir, nitazoxanide, favipiravir, and hydroxychroloquine. In contrast, GRL-0920 exerted potent activity against SARS-CoV-2 (50% effective concentration [EC50] = 2.8 µM) and dramatically reduced the infectivity, replication, and cytopathic effect of SARS-CoV-2 without significant toxicity as examined with immunocytochemistry. Structural modeling shows that indole and chloropyridinyl of the derivatives interact with two catalytic dyad residues of Mpro, Cys145 and His41, resulting in covalent bonding, which was verified using high-performance liquid chromatography-mass spectrometry (HPLC/MS), suggesting that the indole moiety is critical for the anti-SARS-CoV-2 activity of the derivatives. GRL-0920 might serve as a potential therapeutic for coronavirus disease 2019 (COVID-19) and might be optimized to generate more-potent anti-SARS-CoV-2 compounds.IMPORTANCE Targeting the main protease (Mpro) of SARS-CoV-2, we identified two indole-chloropyridinyl-ester derivatives, GRL-0820 and GRL-0920, active against SARS-CoV-2, employing RNA-qPCR and immunocytochemistry and show that the two compounds exerted potent activity against SARS-CoV-2. While GRL-0820 and remdesivir blocked SARS-CoV-2 infection, viral breakthrough occurred as examined with immunocytochemistry. In contrast, GRL-0920 completely blocked the infectivity and cytopathic effect of SARS-CoV-2 without significant toxicity. Structural modeling showed that indole and chloropyridinyl of the derivatives interacted with two catalytic dyad residues of Mpro, Cys145 and His41, resulting in covalent bonding, which was verified using HPLC/MS. The present data should shed light on the development of therapeutics for COVID-19, and optimization of GRL-0920 based on the present data is essential to develop more-potent anti-SARS-CoV-2 compounds for treating COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pneumonia, Viral / Coronavirus Infections / Betacoronavirus / Indoles Limits: Animals Language: English Year: 2020 Document Type: Article Affiliation country: MBio.01833-20

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pneumonia, Viral / Coronavirus Infections / Betacoronavirus / Indoles Limits: Animals Language: English Year: 2020 Document Type: Article Affiliation country: MBio.01833-20