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

Harvard University, Cambridge, Massachusetts, United States
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 04/2007; 354(4):872-8. DOI: 10.1016/j.bbrc.2007.01.071
Source: PubMed


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.

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Available from: Sylvia Lee-Huang, Sep 06, 2014
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    • "Hydroxytyrosol (HT) is a small-molecule phenolic compound found in the leaves and fruits of olive (Olea eurolaea) as a metabolite of oleuropein (Ole), which is one of the major polyphenolic components of olive products (Fig. 1). HT can be purified from olive products (Ciafardini et al., 1994; Lee-Huang et al., 2007a; Visioli et al., 1998a), and can also be prepared by chemical synthesis (Capasso et al., 1999; Espín et al., 2001; Lee-Huang et al., 2007a; Tuck et al., 2000). The polyphenolic compounds contained in olive leaf extracts and olive oils have been reported to exert various bioactivities, including antioxidant (Coni et al., 2000; Visioli et al., 1995, 1998a,b, 2001), anti-inflammatory (Beauchamp et al., 2005; Bitler et al., 2005; Pacheco et al., 2007), and antimicrobial activities against bacteria, fungi, and mycoplasma (Aziz et al., 1998; Bisignano et al., 1999; Furneri et al., 2002). "
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    ABSTRACT: Hydroxytyrosol (HT), a small-molecule phenolic compound, inactivated influenza A viruses including H1N1, H3N2, H5N1, and H9N2 subtypes. HT also inactivated Newcastle disease virus but not bovine rotavirus, and fowl adenovirus, suggesting that the mechanism of the antiviral effect of HT might require the presence of a viral envelope. Pretreatment of MDCK cells with HT did not affect the propagation of H9N2 virus subsequently inoculated onto the cells, implying that HT targets the virus but not the host cell. H9N2 virus inactivated with HT retained unaltered hemagglutinating activity and bound to MDCK cells in a manner similar to untreated virus. Neuraminidase activity in the HT-treated virus also remained unchanged. However, in the cells inoculated with HT-inactivated H9N2 virus, neither viral mRNA nor viral protein was detected. Electron microscopic analysis revealed morphological abnormalities in the HT-treated H9N2 virus. Most structures found in the HT-treated virus were atypical of influenza virions, and localization of hemagglutinin was not necessarily confined on the virion surface. These observations suggest that the structure of H9N2 virus could be disrupted by HT.
    Full-text · Article · Aug 2009 · Antiviral research
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    • "In addition, it protects against atherosclerosis and prevents diabetic neuropathies. The anti HIV effect of these compounds has been investigated (Markin et al., 2003; Micol et al., 2005; Ranalli et al., 2006; Lee-Huang et al., 2007a,b). Olive leaves have to be dried for the purpose of using as an ingredient in dry mixes, for extracting phenolics having antioxidant properties and for use in olive leaf tea, so drying is a critical process in olive leaf treatment. "
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    ABSTRACT: Recently, the interest in olive leaves has increased due to its high phenolic content. Olive leaves have a high potential for industrial exploitation in the food industry and drying is the main process in olive leaf treatment. In this study, response surface methodology was used to optimize operating conditions of the drying of olive leaves in a tray drier and desirability function used as the methodology for the optimization. Optimization factors were air temperature (40–60 °C), air velocity (0.5–1.5 m/s) and process time (240–480 min) while investigated responses were total phenolic content (PC) and antioxidant activity loss (AC), final moisture content (MC), and exergetic efficiency (η). The optimum conditions for drying of olive leaves in a tray drier were determined to obtain the criteria; minimum PC and AC, and maximum η for MC value below 6% and the optimum condition was found to be the temperature of 51.16 °C with the air velocity of 1.01 m/s for the process time of 298.68 min. At this optimum point, PC, AC, MC and η were found as 10.25%, 41.88%, 6.0% and 65.50%, respectively.
    Full-text · Article · Apr 2009 · Journal of Food Engineering
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