Identification of anthranilic acid derivatives as a novel class of allosteric inhibitors of hepatitis C NS5B polymerase.
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.
Nittoli
Thomas
T
Chemical and Screening Sciences and Infectious Diseases Research, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA.
Curran
Kevin
K
Insaf
Shabana
S
DiGrandi
Martin
M
Orlowski
Mark
M
Chopra
Rajiv
R
Agarwal
Atul
A
Howe
Anita Y M
AY
Prashad
Amar
A
Floyd
M Brawner
MB
Johnson
Bernard
B
Sutherland
Alan
A
Wheless
Karen
K
Feld
Boris
B
O'Connell
John
J
Mansour
Tarek S
TS
Bloom
Jonathan
J
D000494:Allosteric Regulation; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D012093:Replicon; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; D062367:ortho-Aminobenzoates; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase