Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design

Fenghua Wang; Cheng Chen; Wenjie Tan; Kailin Yang; Haitao Yang

doi:10.1038/srep22677

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Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design

Journal article

Open access

Peer reviewed

Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design

Fenghua Wang, Cheng Chen, Wenjie Tan, Kailin Yang and Haitao Yang

Scientific reports, Vol.6(1), pp.22677-22677

03/07/2016

DOI: 10.1038/srep22677

PMCID: PMC4780191

PMID: 26948040

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https://doi.org/10.1038/srep22677View

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Abstract

First identified in The Netherlands in 2004, human coronavirus NL63 (HCoV-NL63) was found to cause worldwide infections. Patients infected by HCoV-NL63 are typically young children with upper and lower respiratory tract infection, presenting with symptoms including croup, bronchiolitis, and pneumonia. Unfortunately, there are currently no effective antiviral therapy to contain HCoV-NL63 infection. CoV genomes encode an integral viral component, main protease (M(pro)), which is essential for viral replication through proteolytic processing of RNA replicase machinery. Due to the sequence and structural conservation among all CoVs, M(pro) has been recognized as an attractive molecular target for rational anti-CoV drug design. Here we present the crystal structure of HCoV-NL63 M(pro) in complex with a Michael acceptor inhibitor N3. Structural analysis, consistent with biochemical inhibition results, reveals the molecular mechanism of enzyme inhibition at the highly conservative substrate-recognition pocket. We show such molecular target remains unchanged across 30 clinical isolates of HCoV-NL63 strains. Through comparative study with M(pro)s from other human CoVs (including the deadly SARS-CoV and MERS-CoV) and their related zoonotic CoVs, our structure of HCoV-NL63 M(pro) provides critical insight into rational development of wide spectrum antiviral therapeutics to treat infections caused by human CoVs.

Antiviral Agents - isolation & purification

Antiviral Agents - metabolism

Binding Sites

Coronavirus NL63, Human - enzymology

Crystallography, X-Ray

Drug Design

Peptide Hydrolases - chemistry

Peptide Hydrolases - metabolism

Protease Inhibitors - chemistry

Protease Inhibitors - metabolism

Protein Binding

Protein Conformation

Details

Title: Subtitle: Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design
Creators: Fenghua Wang - Tianjin University
Cheng Chen - Tianjin University
Wenjie Tan - National Institute for Viral Disease Control and Prevention
Kailin Yang - Cleveland Clinic Lerner College of Medicine
Haitao Yang - Tianjin International Joint Academy of Biomedicine
Resource Type: Journal article
Publication Details: Scientific reports, Vol.6(1), pp.22677-22677
DOI: 10.1038/srep22677
PMID: 26948040
PMCID: PMC4780191
ISSN: 2045-2322
eISSN: 2045-2322
Language: English
Date published: 03/07/2016
Academic Unit: Radiation Oncology
Record Identifier: 9984696708502771

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