title: Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. fusion [corrected] inhibition.
abstract: We have identified oleuropein (Ole) and hydroxytyrosol (HT) as a unique class of HIV-1 inhibitors from olive leaf extracts effective against viral fusion and integration. We used molecular docking simulation to study the interactions of Ole and HT with viral targets. We find that Ole and HT bind to the conserved hydrophobic pocket on the surface of the HIV-gp41 fusion domain by hydrogen bonds with Q577 and hydrophobic interactions with I573, G572, and L568 on the gp41 N-terminal heptad repeat peptide N36, interfering with formation of the gp41 fusion-active core. To test and confirm modeling predications, we examined the effect of Ole and HT on HIV-1 fusion complex formation using native polyacrylamide gel electrophoresis and circular dichroism spectroscopy. Ole and HT exhibit dose-dependent inhibition on HIV-1 fusion core formation with EC(50)s of 66-58nM, with no detectable toxicity. Our findings on effects of HIV-1 integrase are reported in the subsequent article.
authors.affiliation: Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA. sylvia.lee-huang@med.nyu.edu
authors.forename: Sylvia
authors.initials: S
authors.lastname: Lee-Huang
authors.forename: Philip Lin
authors.initials: PL
authors.lastname: Huang
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhang
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Lee
authors.forename: Ju
authors.initials: J
authors.lastname: Bao
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Sun
authors.forename: Young-Tae
authors.initials: YT
authors.lastname: Chang
authors.forename: John
authors.initials: J
authors.lastname: Zhang
authors.forename: Paul Lee
authors.initials: PL
authors.lastname: Huang
mesh_terms: D002853:Chromatography, Liquid; D002942:Circular Dichroism; D004591:Electrophoresis, Polyacrylamide Gel; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D057888:Iridoid Glucosides; D039823:Iridoids; D013058:Mass Spectrometry; D008958:Models, Molecular; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D011714:Pyrans / Q000302:isolation & purification* / Q000494:pharmacology
chemical_list: D015700:HIV Envelope Protein gp41; D019428:HIV Integrase Inhibitors; D057888:Iridoid Glucosides; D039823:Iridoids; D011714:Pyrans; C005975:3,4-dihydroxyphenylethanol; C002769:oleuropein; D010626:Phenylethyl Alcohol