Abstract
The anti-HIV-1 activity of mangiferin was evaluated. Mangiferin can inhibit HIV-1ⅢB induced syncytium formation at non-cytotoxic concentrations, with a 50% effective concentration (EC50) at 16.90 μM and a therapeutic index (TI) above 140. Mangiferin also showed good activities in other laboratory-derived strains, clinically isolated strains and resistant HIV-1 strains. Mechanism studies revealed that mangiferin might inhibit the HIV-1 protease, but is still effective against HIV peptidic protease inhibitor resistant strains. A combination of docking and pharmacophore methods clarified possible binding modes of mangiferin in the HIV-1 protease. The pharmacophore model of mangiferin consists of two hydrogen bond donors and two hydrogen bond acceptors. Compared to pharmacophore features found in commercially available drugs, three pharmacophoric elements matched well and one novel pharmacophore element was observed. Moreover, molecular docking analysis demonstrated that the pharmacophoric elements play important roles in binding HIV-1 protease. Mangiferin is a novel nonpeptidic protease inhibitor with an original structure that represents an effective drug development strategy for combating drug resistance.
Highlights
The development of antiretroviral therapies to fight human immunodeficiency virus type 1 (HIV-1)infection has led to a significant decrease in mortality and morbidity among infected populations.the emergence of viral resistant strains to drugs is causing serious clinical and public health problems throughout the world
The results indicated that this compound exhibited low cytotoxicity on C8166, MT-4, chronically-infected H9 cells and Peripheral blood mononuclear cells (PBMCs), and the 50% cytotoxic concentration (CC50) values were all above 1,000 μg/mL
The antiviral activities of mangiferin were observed to primary HIV-1 isolate and resistant strains
Summary
The development of antiretroviral therapies to fight human immunodeficiency virus type 1 (HIV-1). TPV is the only approved nonpeptidic protease inhibitor (NPPI) with potent in vitro activity against a variety of HIV-1 laboratory strains, clinical isolates and PI-resistant viruses [12]. The pharmacology of mangiferin is gaining increased attention owing to its modulating effects on oxidative mechanisms in various disorders [14,15,16,17,18] This compound has been shown to exhibit antitumor [19], antiviral [20,21,22], immunomodulatory [19,23,24] and radioprotective [18] activities under different experimental conditions. The CDOCKER algorithm [25] was employed to investigate a possible binding manner of mangiferin in HIV-1 PR These results revealed that the pharmacophore binding characters of mangiferin and the PIs were not completely the same. Because we have already seen inhibitory activities of mangiferin against resistant strains, it represents a novel small molecule PI with exciting prospects for combating drug resistance
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