SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase.
Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochemical potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were determined by X-ray crystallography, and the inhibitors were found to bind in an allosteric binding site separate from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compounds in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b.
Powers
Jay P
JP
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. jppowers@amgen.com
Piper
Derek E
DE
Li
Yang
Y
Mayorga
Veronica
V
Anzola
John
J
Chen
James M
JM
Jaen
Juan C
JC
Lee
Gary
G
Liu
Jinqian
J
Peterson
M Greg
MG
Tonn
George R
GR
Ye
Qiuping
Q
Walker
Nigel P C
NP
Wang
Zhulun
Z
D000495:Allosteric Site; D009189:Avian Myeloblastosis Virus / Q000201:enzymology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001908:Diarrhea Viruses, Bovine Viral / Q000201:enzymology; D008958:Models, Molecular; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012324:RNA-Dependent RNA Polymerase
D012321:DNA-Directed RNA Polymerases; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; D013871:Thiones; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase