title: Identification of halosalicylamide derivatives as a novel class of allosteric inhibitors of HCV NS5B polymerase.
abstract: Halosalicylamide derivatives were identified from high-throughput screening as potent inhibitors of HCV NS5B polymerase. The subsequent structure and activity relationship revealed the absolute requirement of the salicylamide moiety for optimum activity. Methylation of either the hydroxyl group or the amide group of the salicylamide moiety abolished the activity while the substitutions on both phenyl rings are acceptable. The halosalicylamide derivatives were shown to be non-competitive with respect to elongation nucleotide and demonstrated broad genotype activity against genotype 1-3 HCV NS5B polymerases. Inhibitor competition studies indicated an additive binding mode to the initiation pocket that is occupied by the thiadiazine class of compounds and an additive binding mode to the elongation pocket that is occupied by diketoacids, but a mutually exclusive binding mode with respect to the allosteric thumb pocket that is occupied by the benzimidazole class of inhibitors. Therefore, halosalicylamides represent a novel class of allosteric 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: Pamela L
authors.initials: PL
authors.lastname: Donner
authors.forename: John K
authors.initials: JK
authors.lastname: Pratt
authors.forename: Wen W
authors.initials: WW
authors.lastname: Jiang
authors.forename: Teresa
authors.initials: T
authors.lastname: Ng
authors.forename: Vijaya
authors.initials: V
authors.lastname: Gracias
authors.forename: Steve
authors.initials: S
authors.lastname: Baumeister
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wiedeman
authors.forename: Linda
authors.initials: L
authors.lastname: Traphagen
authors.forename: Usha
authors.initials: U
authors.lastname: Warrior
authors.forename: Clarence
authors.initials: C
authors.lastname: Maring
authors.forename: Warren M
authors.initials: WM
authors.lastname: Kati
authors.forename: Stevan W
authors.initials: SW
authors.lastname: Djuric
authors.forename: Akhteruzzaman
authors.initials: A
authors.lastname: Molla
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D012457:Salicylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D012457:Salicylamides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase