Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. fusion [corrected] inhibition.
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.
Lee-Huang
Sylvia
S
Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA. sylvia.lee-huang@med.nyu.edu
Huang
Philip Lin
PL
Zhang
Dawei
D
Lee
Jae Wook
JW
Bao
Ju
J
Sun
Yongtao
Y
Chang
Young-Tae
YT
Zhang
John
J
Huang
Paul Lee
PL
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
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