title: Identification of a novel sulfonamide non-nucleoside reverse transcriptase inhibitor by a phenotypic HIV-1 full replication assay.
abstract: Classical target-based, high-throughput screening has been useful for the identification of inhibitors for known molecular mechanisms involved in the HIV life cycle. In this study, the development of a cell-based assay that uses a phenotypic drug discovery approach based on automated high-content screening is described. Using this screening approach, the antiviral activity of 26,500 small molecules from a relevant chemical scaffold library was evaluated. Among the selected hits, one sulfonamide compound showed strong anti-HIV activity against wild-type and clinically relevant multidrug resistant HIV strains. The biochemical inhibition, point resistance mutations and the activity of structural analogs allowed us to understand the mode of action and propose a binding model for this compound with HIV-1 reverse transcriptase.
authors.affiliation: Institut Pasteur Korea, Seongnam-Si, Gyeonggi-Do, Korea.
authors.forename: Tae-Hee
authors.initials: TH
authors.lastname: Kim
authors.forename: Yoonae
authors.initials: Y
authors.lastname: Ko
authors.forename: Thierry
authors.initials: T
authors.lastname: Christophe
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cechetto
authors.forename: Junwon
authors.initials: J
authors.lastname: Kim
authors.forename: Kyoung-Ae
authors.initials: KA
authors.lastname: Kim
authors.forename: Annette S
authors.initials: AS
authors.lastname: Boese
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Garcia
authors.forename: Denis
authors.initials: D
authors.lastname: Fenistein
authors.forename: Moon Kyeong
authors.initials: MK
authors.lastname: Ju
authors.forename: Junghwan
authors.initials: J
authors.lastname: Kim
authors.forename: Sung-Jun
authors.initials: SJ
authors.lastname: Han
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Vincent
authors.initials: V
authors.lastname: Brondani
authors.forename: Peter
authors.initials: P
authors.lastname: Sommer
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D057166:High-Throughput Screening Assays; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D054852:Small Molecule Libraries; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D054852:Small Molecule Libraries; D013449:Sulfonamides; D012194:RNA-Directed DNA Polymerase