GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection

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, an...

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Autores principales:	Shin-ichiro Hattori, Nobuyo Higshi-Kuwata, Jakka Raghavaiah, Debananda Das, Haydar Bulut, David A. Davis, Yuki Takamatsu, Kouki Matsuda, Nobutoki Takamune, Naoki Kishimoto, Tadashi Okamura, Shogo Misumi, Robert Yarchoan, Kenji Maeda, Arun K. Ghosh, Hiroaki Mitsuya
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	COVID-19 SARS-CoV-2 main protease antiviral agents Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6ecec4952e2541e4822a0d37047d8b35
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spelling	oai:doaj.org-article:6ecec4952e2541e4822a0d37047d8b352021-11-15T15:56:44ZGRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection10.1128/mBio.01833-202150-7511https://doaj.org/article/6ecec4952e2541e4822a0d37047d8b352020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01833-20https://doaj.org/toc/2150-7511ABSTRACT 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.Shin-ichiro HattoriNobuyo Higshi-KuwataJakka RaghavaiahDebananda DasHaydar BulutDavid A. DavisYuki TakamatsuKouki MatsudaNobutoki TakamuneNaoki KishimotoTadashi OkamuraShogo MisumiRobert YarchoanKenji MaedaArun K. GhoshHiroaki MitsuyaAmerican Society for MicrobiologyarticleCOVID-19SARS-CoV-2main proteaseantiviral agentsMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	COVID-19 SARS-CoV-2 main protease antiviral agents Microbiology QR1-502
spellingShingle	COVID-19 SARS-CoV-2 main protease antiviral agents Microbiology QR1-502 Shin-ichiro Hattori Nobuyo Higshi-Kuwata Jakka Raghavaiah Debananda Das Haydar Bulut David A. Davis Yuki Takamatsu Kouki Matsuda Nobutoki Takamune Naoki Kishimoto Tadashi Okamura Shogo Misumi Robert Yarchoan Kenji Maeda Arun K. Ghosh Hiroaki Mitsuya GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection
description	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.
format	article
author	Shin-ichiro Hattori Nobuyo Higshi-Kuwata Jakka Raghavaiah Debananda Das Haydar Bulut David A. Davis Yuki Takamatsu Kouki Matsuda Nobutoki Takamune Naoki Kishimoto Tadashi Okamura Shogo Misumi Robert Yarchoan Kenji Maeda Arun K. Ghosh Hiroaki Mitsuya
author_facet	Shin-ichiro Hattori Nobuyo Higshi-Kuwata Jakka Raghavaiah Debananda Das Haydar Bulut David A. Davis Yuki Takamatsu Kouki Matsuda Nobutoki Takamune Naoki Kishimoto Tadashi Okamura Shogo Misumi Robert Yarchoan Kenji Maeda Arun K. Ghosh Hiroaki Mitsuya
author_sort	Shin-ichiro Hattori
title	GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection
title_short	GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection
title_full	GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection
title_fullStr	GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection
title_full_unstemmed	GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection
title_sort	grl-0920, an indole chloropyridinyl ester, completely blocks sars-cov-2 infection
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/6ecec4952e2541e4822a0d37047d8b35
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GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection

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