Tietjen Ian, Ntie-Kang Fidele, Mwimanzi Philip, Onguéné Pascal Amoa, Scull Margaret A, Idowu Thomas Oyebode, Ogundaini Abiodun Oguntuga, Meva'a Luc Mbaze, Abegaz Berhanu M, Rice Charles M, Andrae-Marobela Kerstin, Brockman Mark A, Brumme Zabrina L, Fedida David
Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, BC, Canada; Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
Department of Chemistry, Chemical and Bioactivity Information Centre, Faculty of Science, University of Buea, Buea, Cameroon.
PLoS One. 2015 Apr 1;10(4):e0121099. doi: 10.1371/journal.pone.0121099. eCollection 2015.
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.
在撒哈拉以南非洲部分地区等资源有限的地区，艾滋病毒负担持续存在，再加上现有抗逆转录病毒疗法存在不良反应和耐药性潜在风险，凸显了识别新型艾滋病毒抑制剂的必要性。在此，我们对泛非天然产物库中的分子进行了虚拟筛选，该库是非洲大陆最大的药用植物衍生纯化合物集合。我们鉴定出了八种分子，它们与已报道的Vpu相互作用分子结构相似，Vpu是一种具有离子通道活性的HIV-1辅助蛋白。通过使用CD4+T细胞系和外周血单核细胞进行体外HIV-1复制试验，我们证实了两种化合物异荭草素A-2和波弟宁具有抗病毒活性且细胞毒性极小。值得注意的是，异荭草素A-2对编码赋予蛋白酶、非核苷逆转录酶或整合酶抑制剂耐药性的患者来源突变的重组HIV-1毒株仍具有抑制活性。此外，异荭草素A-2在抑制缺乏Vpu的HIV-1复制方面效果较差，这支持该蛋白可能是直接或间接靶点。相比之下，波弟宁对一种蛋白酶抑制剂耐药的HIV-1毒株效果较差。异荭草素A-2和波弟宁还均抑制丙型肝炎病毒（HCV）的体外复制。然而，先前报道的Vpu抑制剂BIT-225在HIV-1和HCV复制试验中表现出抗病毒活性，但也具有细胞毒性。我们的研究确定了源自非洲植物的纯化合物，它们对在世界资源有限地区造成严重影响的病毒具有潜在的新活性。
