3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice

Athri D Rathnayake; Jian Zheng; Yunjeong Kim; Krishani Dinali Perera; Samantha Mackin; David K Meyerholz; Maithri M Kashipathy; Kevin P Battaile; Scott Lovell; Stanley Perlman; William C Groutas; Kyeong-Ok Chang

doi:10.1126/scitranslmed.abc5332

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3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice

Journal article

Open access

Peer reviewed

3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice

Athri D Rathnayake, Jian Zheng, Yunjeong Kim, Krishani Dinali Perera, Samantha Mackin, David K Meyerholz, Maithri M Kashipathy, Kevin P Battaile, Scott Lovell, Stanley Perlman, …

Science translational medicine, Vol.12(557), p.eabc5332

08/19/2020

DOI: 10.1126/scitranslmed.abc5332

PMCID: PMC7574915

PMID: 32747425

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https://doi.org/10.1126/scitranslmed.abc5332View

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Abstract

Pathogenic coronaviruses are a major threat to global public health, as exemplified by severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emerged SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). We describe herein the structure-guided optimization of a series of inhibitors of the coronavirus 3C-like protease (3CLpro), an enzyme essential for viral replication. The optimized compounds were effective against several human coronaviruses including MERS-CoV, SARS-CoV, and SARS-CoV-2 in an enzyme assay and in cell-based assays using Huh-7 and Vero E6 cell lines. Two selected compounds showed antiviral effects against SARS-CoV-2 in cultured primary human airway epithelial cells. In a mouse model of MERS-CoV infection, administration of a lead compound 1 day after virus infection increased survival from 0 to 100% and reduced lung viral titers and lung histopathology. These results suggest that this series of compounds has the potential to be developed further as antiviral drugs against human coronaviruses.

Cysteine Endopeptidases - chemistry

Pandemics

Species Specificity

Coronavirus Infections - drug therapy

Humans

Pneumonia, Viral - drug therapy

Coronavirus 3C Proteases

Crystallography, X-Ray

Male

COVID-19

Microbial Sensitivity Tests

Protease Inhibitors - pharmacology

Lung - virology

SARS-CoV-2

Viral Nonstructural Proteins - chemistry

Antiviral Agents - chemistry

Betacoronavirus - physiology

Vero Cells

Disease Models, Animal

Cell Line

Virus Replication - drug effects

Antiviral Agents - pharmacology

Lung - pathology

Chlorocebus aethiops

Translational Medical Research

Betacoronavirus - drug effects

Middle East Respiratory Syndrome Coronavirus - drug effects

Models, Molecular

Protease Inhibitors - chemistry

Mice, Transgenic

Static Electricity

Animals

Coronavirus Infections - virology

Small Molecule Libraries

Coronavirus Infections - pathology

Mice

In Vitro Techniques

Viral Load - drug effects

Viral Nonstructural Proteins - antagonists & inhibitors

Pneumonia, Viral - virology

Middle East Respiratory Syndrome Coronavirus - physiology

Details

Title: Subtitle: 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice
Creators: Athri D Rathnayake - Department of Chemistry, Wichita State University, Wichita, KS 67260, USA
Jian Zheng - Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA
Yunjeong Kim - Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
Krishani Dinali Perera - Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
Samantha Mackin - Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA
David K Meyerholz - Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
Maithri M Kashipathy - Protein Structure Laboratory, University of Kansas, Lawrence, KS 66045, USA
Kevin P Battaile - NYX, New York Structural Biology Center, Upton, NY 11973, USA
Scott Lovell - Protein Structure Laboratory, University of Kansas, Lawrence, KS 66045, USA
Stanley Perlman - Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA. kchang@vet.ksu.edu stanley-perlman@uiowa.edu bill.groutas@wichita.edu
William C Groutas - Department of Chemistry, Wichita State University, Wichita, KS 67260, USA. kchang@vet.ksu.edu stanley-perlman@uiowa.edu bill.groutas@wichita.edu
Kyeong-Ok Chang - Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA. kchang@vet.ksu.edu stanley-perlman@uiowa.edu bill.groutas@wichita.edu
Resource Type: Journal article
Publication Details: Science translational medicine, Vol.12(557), p.eabc5332
DOI: 10.1126/scitranslmed.abc5332
PMID: 32747425
PMCID: PMC7574915
NLM abbreviation: Sci Transl Med
ISSN: 1946-6234
eISSN: 1946-6242
Publisher: United States
Grant note: R01 AI109039 / NIAID NIH HHS P30 GM110761 / NIGMS NIH HHS R01 AI129269 / NIAID NIH HHS P01 AI060699 / NIAID NIH HHS R01 AI130092 / NIAID NIH HHS
Language: English
Date published: 08/19/2020
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9984070508802771

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