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

Harvard University, Cambridge, Massachusetts, United States
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 04/2007; 354(4):879-84. DOI: 10.1016/j.bbrc.2007.01.058
Source: PubMed


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 including 3'-processing, strand transfer, and disintegration. Ole and HT exhibit dose-dependent inhibition on all three activities, with EC(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.

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Available from: Sylvia Lee-Huang, Sep 06, 2014
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    • "One of the suspected targets for OLE action is HIV-1 gp41 which is responsible for HIV entry into normal cells. In order to establish HIV protein targets of OLE and its inhibitory action at molecular level, a joint theoretical and experimental effort has been carried out to help achieve this goal [12]. OLE is known to contain a mixture of polyphenolic compounds, among them oleuropein, oleuropein aglycone, elenolic acid and hydroxytyrosol (see Fig. 1), which are readily absorbed and bioavailable. "
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    ABSTRACT: Recent experimental study found that OLE (olive leaf extract) has anti-HIV activity by blocking the HIV virus entry to host cells [Lee-Huang, S., Zhang, L., Huang, P.L., Chang, Y. and Huang, P.L. (2003) Anti-HIV activity of olive leaf extract (OLE) and modulation of host cell gene expression by HIV-1 infection and OLE treatment. Biochem. Biophys. Res. Commun. 307, 1029; Lee-Huang, S., Huang, P.L., Zhang, D., Lee, J.W., Bao, J., Sun, Y., Chang, Y.-Tae, Zhang, J.Z.H. and Huang, P.L. (2007) Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol. Biochem. Biophys. Res. Commun. 354, 872-878, 879-884]. As part of a joint experimental and theoretical effort, we report here computational study to help identify and characterize the binding complexes of several main compounds of OLE (olive leaf extract) to HIV-1 envelop protein gp41. A number of possible binding modes are found by docking oleuropein and its metabolites, aglycone, elenolic acid and hydroxytyrosol, onto the hydrophobic pocket on gp41. Detailed OLE-gp41 binding interactions and free energies of binding are obtained through molecular dynamics simulation and MM-PBSA calculation. Specific molecular interactions in our predicted OLE/gp41 complexes are identified and hydroxytyrosol is identified to be the main moiety for binding to gp41. This computational study complements the corresponding experimental investigation and helps establish a good starting point for further refinement of OLE-based gp41 inhibitors.
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    ABSTRACT: The inhibitors involved in the lactic acid fermentation of table olives were investigated in aseptic olive brines of the Manzanilla and Gordal varieties. Phenolic and oleosidic compounds in these brines were identified by high-performance liquid chromatography with ultraviolet and electrospray ionization mass spectrometry detection, and several substances were also characterized by nuclear magnetic resonance. Among these compounds, the dialdehydic form of decarboxymethyl elenolic acid linked to hydroxytyrosol showed the strongest antilactic acid bacteria activity, and its presence in brines could explain the growth inhibition of these microorganisms during olive fermentation. However, it was found that the dialdehydic form of decarboxymethyl elenolic acid, identified for the first time in table olives, and an isomer of oleoside 11-methyl ester were also effective against Lactobacillus pentosus and can, therefore, contribute to the antimicrobial activity of olive brines. It must also be stressed that the three new inhibitors discovered in table olive brines exerted a more potent antibacterial activity than the well-studied oleuropein and hydroxytyrosol.
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