Screening of the Pan-African natural product library identifies ixoratannin A-2 and boldine as novel HIV-1 inhibitors.
Screening of the Pan-African natural product library identifies ixoratannin A-2 and boldine as novel HIV-1 inhibitors.
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DOI：
10.1371/journal.pone.0121099
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Fedida D
中科院分区：
文献类型：
--
作者：
Tietjen I;Ntie-Kang F;Mwimanzi P;Onguéné PA;Scull MA;Idowu TO;Ogundaini AO;Meva'a LM;Abegaz BM;Rice CM;Andrae-Marobela K;Brockman MA;Brumme ZL;Fedida D
艾滋病毒在资源有限的地区，如撒哈拉以南非洲部分地区继续造成负担，加上对现有抗逆转录病毒疗法产生抗药性的不利影响和潜在风险，突出表明需要确定新的艾滋病毒抑制剂。在这里，我们对来自泛非天然产物库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库。我们确定了8个分子的结构相似性，以报告的相互作用的Vpu，HIV-1的辅助蛋白与报告的离子通道活性。使用体外HIV-1复制试验与CD 4 + T细胞系和外周血单核细胞，我们证实了两种化合物，ixoratannin A-2和boldine的抗病毒活性和最小的细胞毒性。值得注意的是，ixoratannin A-2保留了对重组HIV-1菌株的抑制活性，这些重组HIV-1菌株编码患者来源的突变，这些突变赋予对蛋白酶、非核苷逆转录酶或整合酶抑制剂的抗性。此外，ixoratannin A-2在抑制缺乏Vpu的HIV-1复制方面效果较差，支持这种蛋白质作为可能的直接或间接靶标。相比之下，boldine对蛋白酶催化剂耐药的HIV-1菌株的有效性较低。ixoratannin A-2和boldine在体外也抑制丙型肝炎病毒（HCV）的复制。然而，BIT-225，一种先前报道的Vpu抑制剂，在HIV-1和HCV复制试验中表现出抗病毒活性和细胞毒性。我们的工作确定了来自非洲植物的纯化合物，这些化合物具有对抗病毒的潜在新活性，这些病毒不成比例地折磨着世界上资源有限的地区。
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.
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影响因子：
3.8
作者：
Idowu, Thomas Oyebode;Ogundaini, Abiodun Oguntuga;Abegaz, Berhanu Molla
通讯作者：
Abegaz, Berhanu Molla
DOI：
10.1097/qai.0b013e3181fe9450
发表时间：
2011-02-01
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
--
作者：
Brumme ZL;Li C;Miura T;Sela J;Rosato PC;Brumme CJ;Markle TJ;Martin E;Block BL;Trocha A;Kadie CM;Allen TM;Pereyra F;Heckerman D;Walker BD;Brockman MA
通讯作者：
Brockman MA
影响因子：
3.7
作者：
Bolduan, Sebastian;Votteler, Joerg;Schubert, Ulrich
通讯作者：
Schubert, Ulrich
影响因子：
4.9
作者：
Ewart, GD;Nasr, N;Gage, PW
通讯作者：
Gage, PW
影响因子：
1.5
作者：
GIBBS, JS;REGIER, DA;DESROSIERS, RC
通讯作者：
DESROSIERS, RC