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Title: Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Integrase 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{sub 50}s of 66-58 nM, with no detectable toxicity. Our findings on effects of HIV-1 integrase are reported in the subsequent article.

Authors:
 [1];  [2];  [3];  [4];  [4];  [3];  [4];  [4];  [5]
  1. Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States). E-mail: sylvia.lee-huang@med.nyu.edu
  2. American Biosciences, Boston, MA 02114 (United States)
  3. Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States)
  4. Department of Chemistry, New York University, New York, NY 10003 (United States)
  5. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 (United States)
Publication Date:
OSTI Identifier:
20979838
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 354; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2007.01.071; PII: S0006-291X(07)00081-2; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AIDS; AIDS VIRUS; DICHROISM; ELECTROPHORESIS; GELS; INHIBITION; OLIVES; PEPTIDES; SPECTROSCOPY; STRUCTURE FUNCTIONS; TOXICITY

Citation Formats

Lee-Huang, Sylvia, Huang, Philip Lin, Zhang Dawei, Lee, Jae Wook, Bao Ju, Sun Yongtao, Chang, Young-Tae, Zhang, John, and Huang, Paul Lee. Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Integrase inhibition. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2007.01.071.
Lee-Huang, Sylvia, Huang, Philip Lin, Zhang Dawei, Lee, Jae Wook, Bao Ju, Sun Yongtao, Chang, Young-Tae, Zhang, John, & Huang, Paul Lee. Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Integrase inhibition. United States. doi:10.1016/j.bbrc.2007.01.071.
Lee-Huang, Sylvia, Huang, Philip Lin, Zhang Dawei, Lee, Jae Wook, Bao Ju, Sun Yongtao, Chang, Young-Tae, Zhang, John, and Huang, Paul Lee. Fri . "Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Integrase inhibition". United States. doi:10.1016/j.bbrc.2007.01.071.
@article{osti_20979838,
title = {Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Integrase inhibition},
author = {Lee-Huang, Sylvia and Huang, Philip Lin and Zhang Dawei and Lee, Jae Wook and Bao Ju and Sun Yongtao and Chang, Young-Tae and Zhang, John and Huang, Paul Lee},
abstractNote = {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{sub 50}s of 66-58 nM, with no detectable toxicity. Our findings on effects of HIV-1 integrase are reported in the subsequent article.},
doi = {10.1016/j.bbrc.2007.01.071},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 354,
place = {United States},
year = {Fri Mar 23 00:00:00 EDT 2007},
month = {Fri Mar 23 00:00:00 EDT 2007}
}