Abstract
A series of potent anthranilic acid-based inhibitors of the hepatitis C NS5B polymerase has been identified. The inhibitors bind to a site on NS5B between the thumb and palm regions adjacent to the active site as determined by X-ray crystallography of the enzyme-inhibitor complex. Guided by both molecular modeling and traditional SAR, the enzyme activity of the initial hit was improved by approximately 100-fold, yielding a series of potent and selective NS5B inhibitors with IC50 values as low as 10 nM. These compounds were also inhibitors of the HCV replicon in cultured HUH7 cells.
MeSH terms
-
Allosteric Regulation
-
Antiviral Agents / chemical synthesis*
-
Antiviral Agents / chemistry
-
Antiviral Agents / pharmacology
-
Binding Sites
-
Cell Line
-
Crystallography, X-Ray
-
Hepacivirus / drug effects*
-
Hepacivirus / enzymology
-
Hepacivirus / genetics
-
Humans
-
Models, Molecular
-
Replicon
-
Structure-Activity Relationship
-
Viral Nonstructural Proteins / antagonists & inhibitors*
-
Viral Nonstructural Proteins / chemistry
-
Virus Replication / drug effects
-
ortho-Aminobenzoates / chemical synthesis*
-
ortho-Aminobenzoates / chemistry
-
ortho-Aminobenzoates / pharmacology
Substances
-
Antiviral Agents
-
Viral Nonstructural Proteins
-
ortho-Aminobenzoates
-
NS-5 protein, hepatitis C virus