RESUMEN
The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, combined with adverse effects and potential risks of resistance to existing antiretroviral therapies, emphasize the need to identify new HIV inhibitors. Here we performed a virtual screen of molecules from the pan-African Natural Product Library, the largest collection of medicinal plant-derived pure compounds on the African continent. We identified eight molecules with structural similarity to reported interactors of Vpu, an HIV-1 accessory protein with reported ion channel activity. Using in vitro HIV-1 replication assays with a CD4+ T cell line and peripheral blood mononuclear cells, we confirmed antiviral activity and minimal cytotoxicity for two compounds, ixoratannin A-2 and boldine. Notably, ixoratannin A-2 retained inhibitory activity against recombinant HIV-1 strains encoding patient-derived mutations that confer resistance to protease, non-nucleoside reverse transcriptase, or integrase inhibitors. Moreover, ixoratannin A-2 was less effective at inhibiting replication of HIV-1 lacking Vpu, supporting this protein as a possible direct or indirect target. In contrast, boldine was less effective against a protease inhibitor-resistant HIV-1 strain. Both ixoratannin A-2 and boldine also inhibited in vitro replication of hepatitis C virus (HCV). However, BIT-225, a previously-reported Vpu inhibitor, demonstrated antiviral activity but also cytotoxicity in HIV-1 and HCV replication assays. Our work identifies pure compounds derived from African plants with potential novel activities against viruses that disproportionately afflict resource-limited regions of the world.
Asunto(s)
Aporfinas/farmacología , Productos Biológicos/química , VIH-1/efectos de los fármacos , Proantocianidinas/farmacología , Aporfinas/química , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/virología , Línea Celular , Farmacorresistencia Viral , Guanidinas/farmacología , VIH-1/fisiología , Hepacivirus/efectos de los fármacos , Hepacivirus/fisiología , Proteínas del Virus de la Inmunodeficiencia Humana/antagonistas & inhibidores , Proteínas del Virus de la Inmunodeficiencia Humana/metabolismo , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/virología , Simulación del Acoplamiento Molecular , Proantocianidinas/química , Pirazoles/farmacología , Proteínas Reguladoras y Accesorias Virales/antagonistas & inhibidores , Proteínas Reguladoras y Accesorias Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Phytochemical investigation of the ethyl acetate fraction of the methanol extract of the leaves of Ixora coccinea led to the isolation and identification of an A-type trimeric proanthocyanidin epicatechin-(2ßâOâ7, 4ßâ8)-epicatechin-(5âOâ2ß, 6â4ß)-epicatechin named ixoratannin A-2 along with seven known compounds, epicatechin, procyanidin A2, cinnamtannin B-1, and four flavon-3-ol rhamnosides viz: kaempferol-7-O-α-L-rhamnnoside, kaempferol-3-O-α-L-rhamnoside, quercetin-3-O-α-L-rhamnopyranoside, and kaempferol-3,7-O-α-L-dirhamnoside. The structures were elucidated by the application of IR, UV, MS, 1D-, and 2D-NMR spectroscopic analyses and by comparison with literature data. Antioxidant evaluation of isolated compounds revealed that ixoratannin A-2 and cinnamtannin B-1 were the most active compounds in DPPH, inhibition of lipid peroxidation and nitric oxide radical scavenging assays. Antibacterial activities were assessed by means of agar-diffusion assays using Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Bacillus subtilis. All tested compounds inhibited the growth of B. subtilis, while only epicatechin and quercetin-3-O-α-L-rhamnopyranoside inhibited the growth of E. coli.