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

Journal Article · · Science Translational Medicine
 [1];  [2];  [3];  [3];  [2];  [2];  [4];  [5];  [4];  [2];  [1];  [3]
  1. Wichita State Univ., Wichita, KS (United States)
  2. Univ. of Iowa, Iowa City, IA (United States)
  3. Kansas State Univ., Manhattan, KS (United States)
  4. Univ. of Kansas, Lawrence, KS (United States)
  5. New York Structural Biology Center, Upton, NY (United States)
+ Show Author Affiliations
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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1661001
Journal Information:
Science Translational Medicine, Journal Name: Science Translational Medicine Journal Issue: 557 Vol. 12; ISSN 1946-6234
Publisher:
AAASCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (52)

Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies journal November 2017
An efficient synthesis of a key intermediate for the preparation of the rhinovirus protease inhibitor AG7088 via asymmetric dianionic cyanomethylation of N-Boc-l-(+)-glutamic acid dimethyl ester journal September 2001
Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding journal February 2020
Clinicopathologic, Immunohistochemical, and Ultrastructural Findings of a Fatal Case of Middle East Respiratory Syndrome Coronavirus Infection in the United Arab Emirates, April 2014 journal March 2016
Potent inhibition of feline coronaviruses with peptidyl compounds targeting coronavirus 3C-like protease journal February 2013
Protease inhibitors broadly effective against feline, ferret and mink coronaviruses journal December 2018
Potent inhibition of norovirus 3CL protease by peptidyl α-ketoamides and α-ketoheterocycles journal July 2012
Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors journal January 2013
Design, synthesis, and bioevaluation of viral 3C and 3C-like protease inhibitors journal December 2013
Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors journal January 2017
Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element journal April 2018
Prediction and biochemical analysis of putative cleavage sites of the 3C-like protease of Middle East respiratory syndrome coronavirus journal October 2015
Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies journal March 2015
Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 4. Incorporation of P 1 Lactam Moieties as l -Glutamine Replacements journal April 1999
A Novel, Nonaqueous Method for Regeneration of Aldehydes from Bisulfite Adducts journal July 1999
Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys journal March 2016
Coronaviruses — drug discovery and therapeutic options journal February 2016
Improved R-factors for diffraction data analysis in macromolecular crystallography journal April 1997
Principles and approaches for reproducible scoring of tissue stains in research journal May 2018
Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV journal January 2020
Respiratory disease in rhesus macaques inoculated with SARS-CoV-2 journal May 2020
A Novel Coronavirus from Patients with Pneumonia in China, 2019 journal February 2020
Rapid generation of a mouse model for Middle East respiratory syndrome journal March 2014
Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice journal March 2017
Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection journal February 2020
Broad-spectrum coronavirus antiviral drug discovery journal February 2019
Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4 journal October 2015
Global indicators of X-ray data quality journal April 2001
Phaser crystallographic software journal July 2007
Automatic indexing of rotation diffraction patterns journal February 1988
Developments in the CCP 4 molecular-graphics project journal November 2004
Scaling and assessment of data quality journal December 2005
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
XDS journal January 2010
Features and development of Coot journal March 2010
An introduction to data reduction: space-group determination, scaling and intensity statistics journal March 2011
Data processing and analysis with the autoPROC toolbox journal March 2011
Towards automated crystallographic structure refinement with phenix.refine journal March 2012
Structures of the Middle East respiratory syndrome coronavirus 3C-like protease reveal insights into substrate specificity journal April 2015
From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design journal August 2014
Linking Crystallographic Model and Data Quality journal May 2012
Resolving Some Old Problems in Protein Crystallography journal May 2012
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors journal March 2020
Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses journal June 2017
An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice journal April 2020
Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses journal August 2012
Generation of a Transgenic Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease journal January 2015
Broad-Spectrum Inhibitors against 3C-Like Proteases of Feline Coronaviruses and Feline Caliciviruses journal February 2015
ACE2 Receptor Expression and Severe Acute Respiratory Syndrome Coronavirus Infection Depend on Differentiation of Human Airway Epithelia journal December 2005
Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis journal May 2017
Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor journal March 2016
Recent Aspects on the Pathogenesis Mechanism, Animal Models and Novel Therapeutic Interventions for Middle East Respiratory Syndrome Coronavirus Infections journal March 2019

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