Screening of the Pan-African Natural Product Library Identifies Ixoratannin A-2 and Boldine as Novel HIV-1 Inhibitors

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

<b>Reaction of propargyltrimethylsilane magnesium bromide with aldimines: Synthesis of 1-(alkylamino)-2-(trimethylsilyl)but-3-yne</b>

The reaction of propargylsilane magnesium bromide with aldimines provides in some cases, an isomeric mixture of three acetylenic amines <b>1</b>, <b>2</b>, <b>3</b> (<b>1</b> and <b>2</b>, as major products). The reaction has great potential and has been exploited for an efficient synthesis of the pure amine <b>2</b>

Distibution curves for some computed ADME parameters.

<p>(A) logB/B, (B) log<i>K</i>_HSA, (C) logHERG. For subfigure B, the <i>x</i>-axis label is the lower limit of binned data, e.g. −2 is equivalent to −2 to −1. The colour codes are according to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0078085#pone-0078085-g005" target="_blank">Figure 5</a>.</p

Summary of average predicted pharmacokinetic property distributions of the total AfroDb library in comparison with the various subsets.

<p>Summary of average predicted pharmacokinetic property distributions of the total AfroDb library in comparison with the various subsets.</p

2D structures of the three compounds with log <i>P</i> values >14, included in AfroDb.

<p>2D structures of the three compounds with log <i>P</i> values >14, included in AfroDb.</p

Pairwise comparison of mutual relationships between molecular descriptors.

<p>(A) The distribution of the calculated log <i>P</i> versus MW, (B) HBA against MW, (C) HBD against MW and (D) NRB versus MW. LCR represents the Lipinski compliant regions.</p

2D structures of selected promising compounds derived from the African flora and included in AfroDb.

<p>2D structures of selected promising compounds derived from the African flora and included in AfroDb.</p

Sources and biological activities of metabolites with calculated log <i>P</i>>14 found in AfroDb.

<p>Sources and biological activities of metabolites with calculated log <i>P</i>>14 found in AfroDb.</p

Graph distribution of features that determine “drug-likeness”.

<p>(A, B) Histogram of Lipinski violations as a percentage of the AfroDb data set and molar weight distribution, respectively. (C, D, E, F) Distribution curves of the log <i>P</i>, HBA, HBD and NRB, respectively for the 1,008 compounds currently in AfroDb. For subfigure B, the <i>x</i>-axis label is the lower limit of binned data, e.g. 0 is equivalent to 0 to 100.</p

Comparison of property distribution for the two datasets by percentage distributions.

<p>(A) MW, (B) log <i>P</i>, (C) HBA and (D) HBD. DNP in red and AfroDb in blue. For subfigure B, the <i>x</i>-axis label is the lower limit of binned data, e.g. −2 is equivalent to −2 to −1.</p