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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}
}
  • We report molecular modeling and functional confirmation of Ole and HT binding to HIV-1 integrase. Docking simulations identified two binding regions for Ole within the integrase active site. Region I encompasses the conserved D64-D116-E152 motif, while region II involves the flexible loop region formed by amino acid residues 140-149. HT, on the other hand, binds to region II. Both Ole and HT exhibit favorable interactions with important amino acid residues through strong H-bonding and van der Waals contacts, predicting integrase inhibition. To test and confirm modeling predictions, we examined the effect of Ole and HT on HIV-1 integrase activities includingmore » 3'-processing, strand transfer, and disintegration. Ole and HT exhibit dose-dependent inhibition on all three activities, with EC{sub 50}s in the nanomolar range. These studies demonstrate that molecular modeling of target-ligand interaction coupled with structural-activity analysis should facilitate the design and identification of innovative integrase inhibitors and other therapeutics.« less
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  • Cellular infection by HIV-1 is initiated with a binding event between the viral envelope glycoprotein gp120 and the cellular receptor protein CD4. The CD4-gp120 interface is dominated by two hotspots: a hydrophobic gp120 cavity capped by Phe43{sub CD4} and an electrostatic interaction between residues Arg59{sub CD4} and Asp368{sub gp120}. The CD4 mimetic small-molecule NBD-556 (1) binds within the gp120 cavity; however, 1 and related congeners demonstrate limited viral neutralization breadth. Herein, we report the design, synthesis, characterization, and X-ray structures of gp120 in complex with small molecules that simultaneously engage both binding hotspots. The compounds specifically inhibit viral infection ofmore » 42 tier 2 clades B and C viruses and are shown to be antagonists of entry into CD4-negative cells. Dual hotspot design thus provides both a means to enhance neutralization potency of HIV-1 entry inhibitors and a novel structural paradigm for inhibiting the CD4-gp120 protein-protein interaction.« less