Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors.
A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays.
Li
Hui
H
Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr., San Diego, CA 92121, USA. hui.li@pfizer.com
Tatlock
John
J
Linton
Angelica
A
Gonzalez
Javier
J
Borchardt
Allen
A
Dragovich
Peter
P
Jewell
Tanya
T
Prins
Tom
T
Zhou
Ru
R
Blazel
Julie
J
Parge
Hans
H
Love
Robert
R
Hickey
Michael
M
Doan
Chau
C
Shi
Stephanie
S
Duggal
Rohit
R
Lewis
Cristina
C
Fuhrman
Shella
S
D018360:Crystallography, X-Ray; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D006859:Hydrogen / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000737:chemistry
D011753:Pyrones; D017361:Viral Nonstructural Proteins; D006859:Hydrogen; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; D012321:DNA-Directed RNA Polymerases