<p>In all experiments, data are normalized to the replication rate of each HIV-1 strain plu... more <p>In all experiments, data are normalized to the replication rate of each HIV-1 strain plus 0.1% DMSO at Day 4. <b>A-B,</b> effects of ixoratannin A-2 (<b>A</b>) and boldine (<b>B</b>) on HIV-1<sub>NL4-3</sub> and HIV-1<sub>Δvpu</sub> replication. <b>C-D,</b> effects of ixoratannin A-2 (<b>C</b>) and boldine (<b>D</b>) on replication of ARV-resistant HIV-1 strains.*, p < 0.008 vs. HIV-1<sub>NL4-3</sub> at the same concentration of ixoratannin A-2 or boldine. ǂ, p < 0.008 for strain HIV-1<sub>PR+RT</sub> and HIV-1<sub>INT</sub> vs. HIV-1<sub>NL4-3</sub> at same concentration of ixoratannin A-2.</p
<p>Data shown are at Day 4 in the presence of 0.1 μM of established ARVs, relative to the r... more <p>Data shown are at Day 4 in the presence of 0.1 μM of established ARVs, relative to the replication rate of each HIV-1 strain in the presence of 0.1% DMSO vehicle control. *, p < 0.004 vs. HIV-1<sub>NL4-3</sub> replication.</p
<p><b>A,</b> Cell viability at 72 h post-infection in the presence of compounds... more <p><b>A,</b> Cell viability at 72 h post-infection in the presence of compounds at defined concentrations. Data are normalized to the percent of viable cells in a HCV-infected culture plus 0.1% DMSO. <b>B,</b> HCV replication at 72 h post-infection in the presence of compounds. Data are normalized to percent HCV-infected cells plus 0.1% DMSO.</p
<p>Distribution of Lipinski parameters for the p-ANAPL library; (A) Bar chart showing the n... more <p>Distribution of Lipinski parameters for the p-ANAPL library; (A) Bar chart showing the number of Lipinski violations, (B) Bar chart showing the MW parameter, (C) Plot of the lipophilicity parameter, (D) Plot of the HBA parameter, (E) Plot of the HBD parameter, and (F) Plot of the NRB parameter.</p
<p><b>A,</b> CEM-GXR cell viability at Day 4 in the presence of p-ANAPL compoun... more <p><b>A,</b> CEM-GXR cell viability at Day 4 in the presence of p-ANAPL compounds at defined concentrations. Data are normalized to the percent of viable cells in an HIV-1<sub>NL4-3</sub>-infected culture plus 0.1% DMSO. <b>B,</b> HIV-1 replication in CEM-GXR cells at Day 4 in the presence of compounds. Data are normalized to percent HIV-1<sub>NL4-3</sub>-infected cells plus 0.1% DMSO. Dose-response plots of ixoratannin A-2 and boldine are highlighted with blue and green arrows, respectively. <b>C</b>, PBMC viability at Day 5 in the presence of p-ANAPL compounds. Data are normalized to the percent of viable cells in an uninfected culture plus 0.1% DMSO. <b>D</b>, HIV-1 replication in PBMCs at Day 12 in the presence of p-ANAPL compounds, as measured by p24<sup>Gag</sup> levels in cell culture supernatants. Data are normalized to percent HIV-1<sub>NL4-3</sub>-infected cells plus 0.1% DMSO.</p
<p><b>A,</b> Structures of four molecules predicted to interact with the Vpu io... more <p><b>A,</b> Structures of four molecules predicted to interact with the Vpu ion channel [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0121099#pone.0121099.ref020" target="_blank">20</a>]. <b>B,</b> Alignment of four molecules. Chemical substituents that define a shared pharmacophore are highlighted. <b>C,</b> Eight p-ANAPL molecules containing aspects of the shared pharmacophore. For each compound, root mean square deviation (RMSD) values are shown in parentheses.</p
<p>Chemical structures of selected bioactive natural products from the p-ANAPL library (14 ... more <p>Chemical structures of selected bioactive natural products from the p-ANAPL library (14 to 36).</p
<p>Chemical structures of natural products from the p-ANAPL library with log P > 8 units... more <p>Chemical structures of natural products from the p-ANAPL library with log P > 8 units.</p
The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Af-rica, com... more The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Af-rica, 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 mole-cules 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 cy-totoxicity 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 in...
The potential of anti-malarial compounds derived from African medicinal plants. Part I: A pharmac... more The potential of anti-malarial compounds derived from African medicinal plants. Part I: A pharmacological evaluation of alkaloids and terpenoids Amoa Onguéné et al.
The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new antivir... more The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new antiviral countermeasures. The M2 protein of influenza A is a proton-gated, proton-selective ion channel, which is essential for influenza replication and an established antiviral target. However, all currently circulating influenza A virus strains are now resistant to licensed M2-targeting adamantane drugs, primarily due to the widespread prevalence of an M2 variant encoding a serine to asparagine 31 mutation (S31N). To identify new chemical leads that may target M2(S31N), we performed a virtual screen of molecules from two natural product libraries and identified chebulagic acid as a candidate M2(S31N) inhibitor and influenza antiviral. Chebulagic acid selectively restores growth of M2(S31N)-expressing yeast. Molecular modeling also suggests that chebulagic acid hydrolysis fragments preferentially interact with the highly-conserved histidine residue within the pore of M2(S31N) but not adamant...
This paper describes an analysis of the diversity and chemical toxicity assessment of three chemi... more This paper describes an analysis of the diversity and chemical toxicity assessment of three chemical libraries of compounds from African flora (the p-ANAPL, AfroMalariaDb, and Afro-HIV), respectively containing compounds exhibiting activities against diverse diseases, malaria and HIV. The diversity of the three data sets was done by comparison of the three most important principal components computed from standard molecular descriptors. This was also done by a study of the most common substructures (MCSS keys). Meanwhile, the in silico toxicity predictions were done through the identification of chemical structural alerts using Lhasa's knowledge based Derek system. The results show that the libraries occupy different chemical space and that only an insignificant part of the respective libraries could exhibit toxicities beyond acceptable limits. The predicted toxicities end points for compounds which were predicted to "plausible" were further discussed in the light of a...
The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, comb... more 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 integ...
<p>In all experiments, data are normalized to the replication rate of each HIV-1 strain plu... more <p>In all experiments, data are normalized to the replication rate of each HIV-1 strain plus 0.1% DMSO at Day 4. <b>A-B,</b> effects of ixoratannin A-2 (<b>A</b>) and boldine (<b>B</b>) on HIV-1<sub>NL4-3</sub> and HIV-1<sub>Δvpu</sub> replication. <b>C-D,</b> effects of ixoratannin A-2 (<b>C</b>) and boldine (<b>D</b>) on replication of ARV-resistant HIV-1 strains.*, p < 0.008 vs. HIV-1<sub>NL4-3</sub> at the same concentration of ixoratannin A-2 or boldine. ǂ, p < 0.008 for strain HIV-1<sub>PR+RT</sub> and HIV-1<sub>INT</sub> vs. HIV-1<sub>NL4-3</sub> at same concentration of ixoratannin A-2.</p
<p>Data shown are at Day 4 in the presence of 0.1 μM of established ARVs, relative to the r... more <p>Data shown are at Day 4 in the presence of 0.1 μM of established ARVs, relative to the replication rate of each HIV-1 strain in the presence of 0.1% DMSO vehicle control. *, p < 0.004 vs. HIV-1<sub>NL4-3</sub> replication.</p
<p><b>A,</b> Cell viability at 72 h post-infection in the presence of compounds... more <p><b>A,</b> Cell viability at 72 h post-infection in the presence of compounds at defined concentrations. Data are normalized to the percent of viable cells in a HCV-infected culture plus 0.1% DMSO. <b>B,</b> HCV replication at 72 h post-infection in the presence of compounds. Data are normalized to percent HCV-infected cells plus 0.1% DMSO.</p
<p>Distribution of Lipinski parameters for the p-ANAPL library; (A) Bar chart showing the n... more <p>Distribution of Lipinski parameters for the p-ANAPL library; (A) Bar chart showing the number of Lipinski violations, (B) Bar chart showing the MW parameter, (C) Plot of the lipophilicity parameter, (D) Plot of the HBA parameter, (E) Plot of the HBD parameter, and (F) Plot of the NRB parameter.</p
<p><b>A,</b> CEM-GXR cell viability at Day 4 in the presence of p-ANAPL compoun... more <p><b>A,</b> CEM-GXR cell viability at Day 4 in the presence of p-ANAPL compounds at defined concentrations. Data are normalized to the percent of viable cells in an HIV-1<sub>NL4-3</sub>-infected culture plus 0.1% DMSO. <b>B,</b> HIV-1 replication in CEM-GXR cells at Day 4 in the presence of compounds. Data are normalized to percent HIV-1<sub>NL4-3</sub>-infected cells plus 0.1% DMSO. Dose-response plots of ixoratannin A-2 and boldine are highlighted with blue and green arrows, respectively. <b>C</b>, PBMC viability at Day 5 in the presence of p-ANAPL compounds. Data are normalized to the percent of viable cells in an uninfected culture plus 0.1% DMSO. <b>D</b>, HIV-1 replication in PBMCs at Day 12 in the presence of p-ANAPL compounds, as measured by p24<sup>Gag</sup> levels in cell culture supernatants. Data are normalized to percent HIV-1<sub>NL4-3</sub>-infected cells plus 0.1% DMSO.</p
<p><b>A,</b> Structures of four molecules predicted to interact with the Vpu io... more <p><b>A,</b> Structures of four molecules predicted to interact with the Vpu ion channel [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0121099#pone.0121099.ref020" target="_blank">20</a>]. <b>B,</b> Alignment of four molecules. Chemical substituents that define a shared pharmacophore are highlighted. <b>C,</b> Eight p-ANAPL molecules containing aspects of the shared pharmacophore. For each compound, root mean square deviation (RMSD) values are shown in parentheses.</p
<p>Chemical structures of selected bioactive natural products from the p-ANAPL library (14 ... more <p>Chemical structures of selected bioactive natural products from the p-ANAPL library (14 to 36).</p
<p>Chemical structures of natural products from the p-ANAPL library with log P > 8 units... more <p>Chemical structures of natural products from the p-ANAPL library with log P > 8 units.</p
The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Af-rica, com... more The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Af-rica, 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 mole-cules 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 cy-totoxicity 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 in...
The potential of anti-malarial compounds derived from African medicinal plants. Part I: A pharmac... more The potential of anti-malarial compounds derived from African medicinal plants. Part I: A pharmacological evaluation of alkaloids and terpenoids Amoa Onguéné et al.
The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new antivir... more The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new antiviral countermeasures. The M2 protein of influenza A is a proton-gated, proton-selective ion channel, which is essential for influenza replication and an established antiviral target. However, all currently circulating influenza A virus strains are now resistant to licensed M2-targeting adamantane drugs, primarily due to the widespread prevalence of an M2 variant encoding a serine to asparagine 31 mutation (S31N). To identify new chemical leads that may target M2(S31N), we performed a virtual screen of molecules from two natural product libraries and identified chebulagic acid as a candidate M2(S31N) inhibitor and influenza antiviral. Chebulagic acid selectively restores growth of M2(S31N)-expressing yeast. Molecular modeling also suggests that chebulagic acid hydrolysis fragments preferentially interact with the highly-conserved histidine residue within the pore of M2(S31N) but not adamant...
This paper describes an analysis of the diversity and chemical toxicity assessment of three chemi... more This paper describes an analysis of the diversity and chemical toxicity assessment of three chemical libraries of compounds from African flora (the p-ANAPL, AfroMalariaDb, and Afro-HIV), respectively containing compounds exhibiting activities against diverse diseases, malaria and HIV. The diversity of the three data sets was done by comparison of the three most important principal components computed from standard molecular descriptors. This was also done by a study of the most common substructures (MCSS keys). Meanwhile, the in silico toxicity predictions were done through the identification of chemical structural alerts using Lhasa's knowledge based Derek system. The results show that the libraries occupy different chemical space and that only an insignificant part of the respective libraries could exhibit toxicities beyond acceptable limits. The predicted toxicities end points for compounds which were predicted to "plausible" were further discussed in the light of a...
The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, comb... more 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 integ...
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