title: New class of HIV-1 integrase (IN) inhibitors with a dual mode of action.
abstract: tert-Butoxy-(4-phenyl-quinolin-3-yl)-acetic acids (tBPQA) are a new class of HIV-1 integrase (IN) inhibitors that are structurally distinct from IN strand transfer inhibitors but analogous to LEDGINs. LEDGINs are a class of potent antiviral compounds that interacts with the lens epithelium-derived growth factor (LEDGF) binding pocket on IN and were identified through competition binding against LEDGF. LEDGF tethers IN to the host chromatin and enables targeted integration of viral DNA. The prevailing understanding of the antiviral mechanism of LEDGINs is that they inhibit LEDGF binding to IN, which prevents targeted integration of HIV-1. We showed that in addition to the properties already known for LEDGINs, the binding of tBPQAs to the IN dimer interface inhibits IN enzymatic activity in a LEDGF-independent manner. Using the analysis of two long terminal repeat junctions in HIV-infected cells, we showed that the inhibition by tBPQAs occurs at or prior to the viral DNA 3'-processing step. Biochemical studies revealed that this inhibition operates by compound-induced conformational changes in the IN dimer that prevent proper assembly of IN onto viral DNA. For the first time, tBPQAs were demonstrated to be allosteric inhibitors of HIV-1 IN displaying a dual mode of action: inhibition of IN-viral DNA assembly and inhibition of IN-LEDGF interaction.
authors.affiliation: Gilead Sciences, Inc, Foster City, California 94404, USA. mtsiang@gilead.com
authors.forename: Manuel
authors.initials: M
authors.lastname: Tsiang
authors.forename: Gregg S
authors.initials: GS
authors.lastname: Jones
authors.forename: Anita
authors.initials: A
authors.lastname: Niedziela-Majka
authors.forename: Elaine
authors.initials: E
authors.lastname: Kan
authors.forename: Eric B
authors.initials: EB
authors.lastname: Lansdon
authors.forename: Wayne
authors.initials: W
authors.lastname: Huang
authors.forename: Magdeleine
authors.initials: M
authors.lastname: Hung
authors.forename: Dharmaraj
authors.initials: D
authors.lastname: Samuel
authors.forename: Nikolai
authors.initials: N
authors.lastname: Novikov
authors.forename: Yili
authors.initials: Y
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: Mitchell
authors.forename: Hongyan
authors.initials: H
authors.lastname: Guo
authors.forename: Kerim
authors.initials: K
authors.lastname: Babaoglu
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liu
authors.forename: Romas
authors.initials: R
authors.lastname: Geleziunas
authors.forename: Roman
authors.initials: R
authors.lastname: Sakowicz
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016662:Virus Integration / Q000187:drug effects* / Q000502:physiology
chemical_list: D000085:Acetates; D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; C504649:PSIP1 protein, human; D011804:Quinolines; D014157:Transcription Factors; D019427:HIV Integrase