title: Identification of aryl dihydrouracil derivatives as palm initiation site inhibitors of HCV NS5B polymerase.
abstract: Aryl dihydrouracil derivatives were identified from high throughput screening as potent inhibitors of HCV NS5B polymerase. The aryl dihydrouracil derivatives were shown to be non-competitive with respect to template RNA and elongation nucleotide substrates. They demonstrated genotype 1 specific activity towards HCV NS5B polymerases. Structure activity relationships and genotype specific activities of aryl dihydrouracil derivatives suggested that they bind to the palm initiation nucleotide pocket, a hypothesis which was confirmed by studies with polymerases containing mutations in various inhibitor binding sites. Therefore, aryl dihydrouracil derivatives represent a novel class of palm initiation site inhibitors of HCV NS5B polymerase.
authors.affiliation: Antiviral Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. yaya.liu@abbott.com
authors.forename: Yaya
authors.initials: Y
authors.lastname: Liu
authors.forename: Ben Hock
authors.initials: BH
authors.lastname: Lim
authors.forename: Wen W
authors.initials: WW
authors.lastname: Jiang
authors.forename: Charles A
authors.initials: CA
authors.lastname: Flentge
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Hutchinson
authors.forename: Darold L
authors.initials: DL
authors.lastname: Madigan
authors.forename: John T
authors.initials: JT
authors.lastname: Randolph
authors.forename: Rolf
authors.initials: R
authors.lastname: Wagner
authors.forename: Clarence J
authors.initials: CJ
authors.lastname: Maring
authors.forename: Warren M
authors.initials: WM
authors.lastname: Kati
authors.forename: Akhteruzzaman
authors.initials: A
authors.lastname: Molla
mesh_terms: D019943:Amino Acid Substitution; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D024363:Transcription Initiation Site; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D011480:Protease Inhibitors; D014498:Uracil; D017361:Viral Nonstructural Proteins; C007419:dihydrouracil; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase