Abstract
Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Cell Line / drug effects
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Chemistry Techniques, Synthetic
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Coronavirus 3C Proteases
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Crystallography, X-Ray
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Cysteine Endopeptidases / chemistry
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Cysteine Endopeptidases / metabolism
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Dipeptidyl-Peptidase IV Inhibitors / chemistry
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Dipeptidyl-Peptidase IV Inhibitors / pharmacology
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Dose-Response Relationship, Drug
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Drug Design
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Female
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Macrophages / drug effects
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Macrophages / virology
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Mice, Inbred BALB C
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Models, Molecular
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Norovirus / drug effects
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Norovirus / enzymology*
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Norovirus / pathogenicity
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Peptide Hydrolases / chemistry*
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Peptide Hydrolases / metabolism
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacology*
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Protein Conformation
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Structure-Activity Relationship
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Viral Proteins / antagonists & inhibitors
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Viral Proteins / chemistry*
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Viral Proteins / metabolism
Substances
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Antiviral Agents
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Dipeptidyl-Peptidase IV Inhibitors
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Protease Inhibitors
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Viral Proteins
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Peptide Hydrolases
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Cysteine Endopeptidases
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Coronavirus 3C Proteases
Associated data
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PDB/4XBB
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PDB/4XBC
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PDB/4XBD