Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Integrase inhibition

Journal Article · Fri Mar 23 04:00:00 EDT 2007 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2007.01.071· OSTI ID:20979838

Lee-Huang, Sylvia ^[1]; Huang, Philip Lin ^[2]; Dawei, Zhang ^[1]; Lee, Jae Wook ^[3]; Ju, Bao ^[3]; Yongtao, Sun ^[1]; Chang, Young-Tae ^[3]; Zhang, John ^[3]; Huang, Paul Lee ^[4]

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1. Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States)
2. American Biosciences, Boston, MA 02114 (United States)
3. Department of Chemistry, New York University, New York, NY 10003 (United States)
4. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 (United States)

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.

• OSTI ID: 20979838
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 4 Vol. 354; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AIDS
AIDS VIRUS
DICHROISM
ELECTROPHORESIS
GELS
INHIBITION
OLIVES
PEPTIDES
SPECTROSCOPY
STRUCTURE FUNCTIONS
TOXICITY