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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    • "Oleuropein (Ole, 79) and hydroxytyrosol (HT, 80) from olive leaf extracts were identified as a unique class of HIV-1 inhibitors effective against viral fusion and integration. Molecular docking simulation was used to study the interactions of Ole and HT with viral targets, which facilitates the design and identification of innovative integrase inhibitors and/or fusion inhibitors [101,102]. Three alkylsalicylic acids (81-83), isolated from the CH 2 Cl 2 extracts of the sarcotestas of Ginkgo biloba, were elucidated as a new class of inhibitors against HIV-1 PR and RNase H of HIV-1 RT [103]. "
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    ABSTRACT: Currently, the effect of AIDS single-target chemotherapy is severely compromised by the quick emergence of resistant HIV strains. Highly active antiretroviral therapy (HAART) combines HIV reverse transcriptase inhibitors with protease inhibitors or integrase inhibitors, and successfully suppresses HIV viral load to an undetectable level, dramatically improving the life quality of AIDS patients. However, the benefits of this approach are often compromised by poor patient compliance. Recently, there has been a move toward multicomponent drugs whereby two or more agents are coformulated in a single tablet to make dosing regimes simpler and thereby to improve patient compliance, but there are significant risks involved in the development of multicomponent drugs. Designed multiple ligands (DMLs) therapy as an emerging anti-HIV drug discovery paradigm, using a single entity to inhibit multitargets could yield improved patient compliance, thus reducing the likelihood of drug resistance. The exploration of such multifunctional ligands has proven valuable for anti-HIV leads discovery. However, presently many multifunctional scaffolds were first discovered by serendipity or screening; rational design by combining existing monofunctional scaffolds remains an enormous challenge. A key issue in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. This review of literature examples introduce numerous attractive lead compounds, capable of interfering with different stages of HIV infection and AIDS pathogenesis, which reveals trends and insights that might provide valuable clues for novel anti-HIV drug design and help medicinal chemists discover the next generation of multiple ligands.
    Full-text · Article · Feb 2009 · Current pharmaceutical design
    • "Virgin olive oil (VOO) is unique among other vegetable oils due to its high levels of monounsaturated fatty acids (mainly oleic acid) and to the presence of minor components, such as phenolic compounds (Lerma-García et al., 2009). Recent epidemiological studies have proved that the consumption of olive oil rich in phenolic compounds has a beneficial effect for the treatment or prevention of various types of allergic diseases (Yamada, Zarrouk, & Isoda, 2009) and leads to a reduced risk of cardiovascular disease (Estruch et al., 2006; Fito et al., 2007), neurodegenerative disease (Scarmeas, Stern, Tang, Mayeux, & Luchsinger, 2006; Trichopoulou, Costacou, Bamia, & Trichopoulos, 2003), certain types of cancer (Colomer et al., 2008; Menendez et al., 2007 Menendez et al., , 2008), and HIV-1 infection (Huang et al., 2007). In Tunisia, the second country after the European Union in the olive oil exportation scale, the variety 'Chemlali' contributes to 80% of the national olive oil production and covers a wide geographical area where a wide range of edapho-climatic conditions are prevailing. "
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    ABSTRACT: Eight antibiotics, chlortetracycline, demeclocycline, doxycycline, methacycline, minocycline, oxytetracycline, tetracycline and rolitetracycline, were separated and quantified in Spanish honey extracts of different floral origin using a commercial RP-C18 HPLC column and two different on-line detectors (diode array and electrospray time-of-flight mass spectrometry (ESI-TOF-MS) systems). Operating a linear gradient at a flow of 2 ml min(-1) the HPLC separation of the eight antibiotics was obtained within 10 min with good peak symmetry and an acceptable resolution (2.1) for the critical band pair rolitetracycline and oxytetracycline. Values of the numbers of theoretical plates (N) were comprised between 2328 and 19448 while the limits of detection in honey were within 0.02-1.03 microg kg(-1) in the case of UV detection and 0.05-0.76 microg kg(-1) for ESI-TOF-MS detection (operating in negative mode). A recovery study was carried out by preparing some quality control samples at four levels of concentration (10, 25, 50 and 100 microg kg(-1)) and percentages between 72% and 98% were attained.
    No preview · Article · Jul 2008 · Journal of Chromatography A
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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.
    Full-text · Article · Jul 2007 · FEBS Letters
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