Abstract
Here we report a highly conserved new binding site located at the interface between the protease and helicase domains of the hepatitis C virus (HCV) NS3 protein. Using a chemical lead, identified by fragment screening and structure-guided design, we demonstrate that this site has a regulatory function on the protease activity via an allosteric mechanism. We propose that compounds binding at this allosteric site inhibit the function of the NS3 protein by stabilizing an inactive conformation and thus represent a new class of direct-acting antiviral agents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation / drug effects
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Allosteric Site* / drug effects
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Allosteric Site* / genetics
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Dose-Response Relationship, Drug
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Ligands
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Models, Molecular
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Molecular Structure
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Structure-Activity Relationship
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Viral Nonstructural Proteins / drug effects
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Viral Nonstructural Proteins / genetics
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Viral Nonstructural Proteins / metabolism*
Substances
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Antiviral Agents
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Ligands
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NS3 protein, hepatitis C virus
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Viral Nonstructural Proteins
Associated data
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PDB/4B6E
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PDB/4B6F
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PDB/4B71
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PDB/4B73
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PDB/4B74
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PDB/4B75
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PDB/4B76
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PubChem-Substance/144100018
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PubChem-Substance/144100019
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PubChem-Substance/144100020
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PubChem-Substance/144100021
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PubChem-Substance/144100022
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PubChem-Substance/144100023
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PubChem-Substance/144100024