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.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Antiviral Agents / chemistry
-
Antiviral Agents / pharmacology*
-
Betacoronavirus / drug effects*
-
Betacoronavirus / physiology
-
COVID-19
-
COVID-19 Drug Treatment
-
Cell Line
-
Chlorocebus aethiops
-
Coronavirus 3C Proteases
-
Coronavirus Infections / drug therapy*
-
Coronavirus Infections / pathology
-
Coronavirus Infections / virology*
-
Crystallography, X-Ray
-
Cysteine Endopeptidases / chemistry
-
Disease Models, Animal
-
Humans
-
In Vitro Techniques
-
Lung / pathology
-
Lung / virology
-
Male
-
Mice
-
Mice, Transgenic
-
Microbial Sensitivity Tests
-
Middle East Respiratory Syndrome Coronavirus / drug effects*
-
Middle East Respiratory Syndrome Coronavirus / physiology
-
Models, Molecular
-
Pandemics
-
Pneumonia, Viral / drug therapy*
-
Pneumonia, Viral / virology*
-
Protease Inhibitors / chemistry
-
Protease Inhibitors / pharmacology*
-
SARS-CoV-2
-
Small Molecule Libraries
-
Species Specificity
-
Static Electricity
-
Translational Research, Biomedical
-
Vero Cells
-
Viral Load / drug effects
-
Viral Nonstructural Proteins / antagonists & inhibitors*
-
Viral Nonstructural Proteins / chemistry
-
Virus Replication / drug effects*
Substances
-
Antiviral Agents
-
Protease Inhibitors
-
Small Molecule Libraries
-
Viral Nonstructural Proteins
-
Cysteine Endopeptidases
-
Coronavirus 3C Proteases