Abstract
Human noroviruses are the primary causative agents of acute gastroenteritis and a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. Norovirus 3CL protease plays a vital role in viral replication by generating structural and nonstructural proteins via the cleavage of the viral polyprotein. Thus, molecules that inhibit the viral protease may have potential therapeutic value. We describe herein the structure-based design, synthesis, and in vitro and cell-based evaluation of the first class of oxadiazole-based, permeable macrocyclic inhibitors of norovirus 3CL protease.
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 / chemical synthesis
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology*
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Cell Line
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Cell Membrane Permeability* / drug effects
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Humans
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Macrocyclic Compounds / chemical synthesis
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology*
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Mice
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Models, Molecular
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Molecular Structure
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Norovirus / drug effects*
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Norovirus / enzymology*
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Oxadiazoles / chemical synthesis
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacology*
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Peptide Hydrolases / metabolism*
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Antiviral Agents
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Macrocyclic Compounds
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Oxadiazoles
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Protease Inhibitors
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Peptide Hydrolases