HIV-1 inhibitors that act by mechanisms distinct from existing antiretrovirals can provide novel insights into viral replication and potentially inform development of new therapeutics. Using a multi-cycle HIV-1 replication assay, we screened 252 pure compounds derived from marine invertebrates and microorganisms and identified 6 (actinomycin Z₂, bastadin 6, bengamide A, haliclonacyclamine A + B, keramamine C, neopetrosiamide B) that inhibited HIV-1 with 50% effective concentrations (EC₅₀s) of 3.8 μM or less. The most potent inhibitor, bengamide A, blocked HIV-1 in a T cell line with an EC₅₀ of 0.015 μM and in peripheral blood mononuclear cells with an EC₅₀ of 0.032 μM. Bengamide A was previously described to inhibit NF-κB signaling. Consistent with this mechanism, bengamide A suppressed reporter expression from an NF-κB-driven minimal promoter and an HIV-1 long terminal repeat (LTR) with conserved NF-κB response elements, but lacked activity against an LTR construct with mutation of these elements. In single-cycle HIV-1 infection assays, bengamide A also suppressed viral protein expression when viruses encoded an intact LTR but exhibited minimal activity against those with mutated NF-κB elements. Finally, bengamide A did not inhibit viral DNA accumulation, indicating that it likely acts downstream of this step in HIV-1 replication. Our study identifies multiple new antiviral compounds including an unusually potent inhibitor of HIV-1 gene expression.

通过与现有抗逆转录病毒药物不同的机制起作用的HIV-1抑制剂可以为病毒复制提供新的见解，并有可能为新疗法的开发提供信息。使用多周期HIV-1复制测定法，我们筛选了252种源自海洋无脊椎动物和微生物的纯化合物，并鉴定了6种抑制HIV的化合物（放线菌素Z ₂，巴斯塔丁6，苯甲酰胺A，卤代环素A + B，keramamine C，新石油酰胺B） -1的有效浓度（EC ₅₀ s）的50％等于或小于3.8μM。最有效的抑制剂，苯甲酰胺A，在T细胞系中的HIV ₅₀为0.015μM，在外周血单核细胞中，其EC _50为50，从而阻断了HIV-1的表达。为0.032μM。先前曾描述过Bengamide A可抑制NF-κB信号传导。与此机制一致，苯甲酰胺A抑制了NF-κB驱动的最小启动子和带有保守NF-κB反应元件的HIV-1长末端重复序列（LTR）的报告基因表达，但对具有这些元件突变的LTR构建体缺乏活性。在单周期HIV-1感染检测中，当病毒编码完整的LTR，但对具有突变NF-κB元素的病毒表现出最小的活性时，苯甲酰胺A也会抑制病毒蛋白的表达。最后，苯甲酰胺A不能抑制病毒DNA的积累，表明它可能在HIV-1复制的这一步骤的下游起作用。我们的研究确定了多种新的抗病毒化合物，其中包括一种异常有效的HIV-1基因表达抑制剂。