Abstract
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.
Highlights
While recent advances in antiretroviral therapies (ARVs) have converted HIV to a chronic, manageable condition in many high-income settings, barriers remain for their successful use in low and middle-income countries with high disease burden; for example in parts of sub-Saharan Africa
Drug resistance has been documented to all licensed ARVs [5], and transmission of resistant HIV remains a major concern in many sub-Saharan African nations [6]
Of eight molecules identified in this screen, two were observed to inhibit in vitro HIV-1 replication in a CD4+ T cell line as well as peripheral blood mononuclear cells (PBMCs)
Summary
While recent advances in antiretroviral therapies (ARVs) have converted HIV to a chronic, manageable condition in many high-income settings, barriers remain for their successful use in low and middle-income countries with high disease burden; for example in parts of sub-Saharan Africa. Natural products are a promising but undervalued resource for identifying new antivirals [2] Compounds derived from these sources can encompass structural diversity that falls outside the scope of chemical spaces found in many synthetic chemical screening libraries [1, 7]; as such, they have the potential to act via mechanisms distinct from those of conventional therapies. With this advantage in mind, the pan-African Natural Product Library (p-ANAPL) was formed to provide a centralized resource of pure compounds obtained from local plants with medicinal properties supported by indigenous knowledge [8]. The p-ANAPL represents an opportunity to screen for new inhibitors of pathogens that disproportionately affect countries on the African continent
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