Crystal Structure of Feline Infectious Peritonitis Virus Main Protease in Complex with Synergetic Dual Inhibitors

Fenghua Wang; Cheng Chen; Xuemeng Liu; Kailin Yang; Xiaoling Xu; Haitao Yang

doi:10.1128/JVI.02685-15

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Crystal Structure of Feline Infectious Peritonitis Virus Main Protease in Complex with Synergetic Dual Inhibitors

Journal article

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Crystal Structure of Feline Infectious Peritonitis Virus Main Protease in Complex with Synergetic Dual Inhibitors

Fenghua Wang, Cheng Chen, Xuemeng Liu, Kailin Yang, Xiaoling Xu and Haitao Yang

Journal of virology, Vol.90(4), pp.1910-1917

02/15/2016

DOI: 10.1128/JVI.02685-15

PMCID: PMC4734010

PMID: 26656689

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Abstract

Coronaviruses (CoVs) can cause highly prevalent diseases in humans and animals. Feline infectious peritonitis virus (FIPV) belongs to the genus Alphacoronavirus, resulting in a lethal systemic granulomatous disease called feline infectious peritonitis (FIP), which is one of the most important fatal infectious diseases of cats worldwide. No specific vaccines or drugs have been approved to treat FIP. CoV main proteases (M(pro)s) play a pivotal role in viral transcription and replication, making them an ideal target for drug development. Here, we report the crystal structure of FIPV M(pro) in complex with dual inhibitors, a zinc ion and a Michael acceptor. The complex structure elaborates a unique mechanism of two distinct inhibitors synergizing to inactivate the protease, providing a structural basis to design novel antivirals and suggesting the potential to take advantage of zinc as an adjunct therapy against CoV-associated diseases. Coronaviruses (CoVs) have the largest genome size among all RNA viruses. CoV infection causes various diseases in humans and animals, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). No approved specific drugs or vaccinations are available to treat their infections. Here, we report a novel dual inhibition mechanism targeting CoV main protease (M(pro)) from feline infectious peritonitis virus (FIPV), which leads to lethal systemic granulomatous disease in cats. M(pro), conserved across all CoV genomes, is essential for viral replication and transcription. We demonstrated that zinc ion and a Michael acceptor-based peptidomimetic inhibitor synergistically inactivate FIPV M(pro). We also solved the structure of FIPV M(pro) complexed with two inhibitors, delineating the structural view of a dual inhibition mechanism. Our study provides new insight into the pharmaceutical strategy against CoV M(pro) through using zinc as an adjuvant therapy to enhance the efficacy of an irreversible peptidomimetic inhibitor.

Amino Acid Sequence

Coronavirus, Feline - enzymology

Crystallography, X-Ray

Cysteine Endopeptidases - chemistry

Cysteine Endopeptidases - metabolism

Models, Molecular

Molecular Sequence Data

Protease Inhibitors - chemistry

Protease Inhibitors - metabolism

Protein Binding

Protein Conformation

Zinc - chemistry

Zinc - metabolism

Details

Title: Subtitle: Crystal Structure of Feline Infectious Peritonitis Virus Main Protease in Complex with Synergetic Dual Inhibitors
Creators: Fenghua Wang - Tianjin University
Cheng Chen - Tianjin University
Xuemeng Liu - Hangzhou Normal University
Kailin Yang - Cleveland Clinic Lerner College of Medicine
Xiaoling Xu - Hangzhou Normal University
Haitao Yang - Tianjin University
Resource Type: Journal article
Publication Details: Journal of virology, Vol.90(4), pp.1910-1917
DOI: 10.1128/JVI.02685-15
PMID: 26656689
PMCID: PMC4734010
ISSN: 0022-538X
eISSN: 1098-5514
Language: English
Date published: 02/15/2016
Academic Unit: Radiation Oncology
Record Identifier: 9984696577302771

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