Wohl Virion Centre, MRC Centre for Medical Molecular Virology, UCL, London, UK.
Chem Biol Drug Des. 2010 May;75(5):461-74. doi: 10.1111/j.1747-0285.2010.00956.x.
Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened a library of isoxazolidine and isoxazole sulfonamides and found four compounds that inhibited HIV-1 infection in human CD4+ lymphocytic T cells with no toxicity at IC(90) concentrations. Structure-activity relationship showed that benzyl sulfonamides and a halo-substituted aromatic ring on the heterocycle scaffold were critical for antiretroviral activity. The size and position of the incorporated halogen had a marked effect on the antiretroviral activity. The sulfonamide derivatives had no significant effect on HIV-1 entry, reverse transcription and integration but impaired a step necessary for activation of viral gene expression. This step was Tat-independent, strongly suggesting that the target is a cell factor. A virus partially resistant to the least potent compounds could be selected but could not be propagated in the long term, consistent with the possibility that HIV-1 may be less likely to develop resistance against drugs targeting some host factors. Here, we provide evidence that novel synthetic methods can be applied to develop small molecules with antiretroviral activity that target host factors important for HIV-1 replication.
靶向宿主因子是开发新型抗病毒药物的一种补充策略。我们筛选了异恶唑烷和异恶唑磺酰胺文库，发现了四种化合物，它们在 IC（90）浓度下对人 CD4+淋巴样 T 细胞中的 HIV-1 感染没有毒性。结构-活性关系表明，苯磺酰胺和杂环骨架上的卤代芳烃是抗逆转录病毒活性的关键。杂环上卤素的大小和位置对抗逆转录病毒活性有显著影响。磺酰胺衍生物对 HIV-1 进入、逆转录和整合没有显著影响，但会损害病毒基因表达激活所必需的步骤。这一步骤与 Tat 无关，强烈表明靶标是一种细胞因子。可以选择对最不有效化合物具有部分抗性的病毒，但不能长期繁殖，这与针对某些宿主因子的药物，HIV-1 可能不太可能产生耐药性的可能性一致。在这里，我们提供了证据，表明新的合成方法可用于开发针对 HIV-1 复制的重要宿主因子具有抗逆转录病毒活性的小分子。
