GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection-Reference-Cited by-同舟云学术

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

Published:2020-08-25 Issue:4 Volume:11 Page:
ISSN:2161-2129
Container-title:mBio
language:en
Short-container-title:mBio

Author:

Hattori Shin-ichiro¹,Higshi-Kuwata Nobuyo¹,Raghavaiah Jakka²³,Das Debananda⁴,Bulut Haydar⁴^ORCID,Davis David A.⁵,Takamatsu Yuki¹^ORCID,Matsuda Kouki¹,Takamune Nobutoki⁶,Kishimoto Naoki⁷,Okamura Tadashi⁸,Misumi Shogo⁷,Yarchoan Robert⁵^ORCID,Maeda Kenji¹,Ghosh Arun K.²³,Mitsuya Hiroaki¹⁴⁹^ORCID

Affiliation:

1. Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan

2. Department of Chemistry, Purdue University, West Lafayette, Indiana, USA

3. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA

4. Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

5. Viral Oncology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

6. Kumamoto Innovative Development Organization, Kumamoto University, Kumamoto, Japan

7. Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Science, Kumamoto University, Kumamoto, Japan

8. Department of Laboratory Animal Medicine, National Center for Global Health and Medicine Research Institute, Tokyo, Japan

9. Department of Clinical Sciences, Kumamoto University Hospital, Kumamoto, Japan

Abstract

Targeting the main protease (M pro ) 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 M pro , 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.

Funder

National Institutes of Health

HHS | NIH | National Cancer Institute

National Center for Global Health and Medicine

Publisher

American Society for Microbiology

Subject

Virology,Microbiology

Link

https://journals.asm.org/doi/pdf/10.1128/mBio.01833-20

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