The recent burst of explorations on heat shock protein 90 (HSP90) in virus research supports its emergence as a promising target to overcome the drawbacks of current antiviral therapeutic regimen. In continuation of our efforts towards the discovery of novel anti-retroviral molecules, we designed, synthesized fifteen novels 2-isoxazol-3-yl-acetamide based compounds (2a-o) followed by analysis of their anti-HIV activity and cytotoxicity studies. 2a-b, 2e, 2j, and 2l-m were found to be active with inhibitory potentials >80% at their highest non-cytotoxic concentration (HNC). Further characterization of anti-HIV activity of these molecules suggests that 2l has ∼3.5 fold better therapeutic index than AUY922, the second generation HSP90 inhibitor. The anti-HIV activity of 2l is a cell type, virus isolate and viral load independent phenomena. Interestingly, 2l does not significantly modulate viral enzymes like Reverse Transcriptase (RT), Integrase (IN) and Protease (PR) as compared to their known inhibitors in a cell free in vitro assay system at its HNC. Further, 2l mediated inhibition of HSP90 attenuates HIV-1 LTR driven gene expression. Taken together, structural rationale, modeling studies and characterization of biological activities suggest that this novel scaffold can attenuate HIV-1 replication significantly within the host and thus opens a new horizon to develop novel anti-HIV therapeutic candidates.

中文翻译：

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发现2-异恶唑-3-基-乙酰胺类似物作为具有显着抗HIV活性的热休克蛋白90（HSP90）抑制剂。

最近在病毒研究中对热休克蛋白90（HSP90）的探索激增支持其作为克服当前抗病毒治疗方案的缺点的有希望的靶标的出现。在继续努力探索新型抗逆转录病毒分子的过程中，我们设计，合成了15种基于2-isoxazol-3-yl-acetamide的新型化合物（2a-o），然后分析了它们的抗HIV活性和细胞毒性研究。发现2a-b，2e，2j和2l-m在其最高非细胞毒性浓度（HNC）下具有抑制潜力> 80％的活性。这些分子的抗HIV活性的进一步特征表明2l具有比第二代HSP90抑制剂AUY922好约3.5倍的治疗指数。2l的抗HIV活性是细胞类型，病毒分离株和病毒载量独立现象。有趣的是，在HNC的无细胞体外测定系统中，与它们的已知抑制剂相比，2l不会显着调节病毒酶，例如逆转录酶（RT），整合酶（IN）和蛋白酶（PR）。此外，2l介导的对HSP90的抑制作用减弱了HIV-1 LTR驱动的基因表达。综上所述，结构原理，模型研究和生物学活性表征表明，这种新型支架可以显着减弱宿主内HIV-1的复制，从而为开发新型抗HIV治疗候选物开辟了新视野。HSP90 2l介导的抑制作用减弱了HIV-1 LTR驱动的基因表达。综上所述，结构原理，模型研究和生物学活性表征表明，这种新型支架可以显着减弱宿主内HIV-1的复制，从而为开发新型抗HIV治疗候选物开辟了新视野。HSP90 2l介导的抑制作用减弱了HIV-1 LTR驱动的基因表达。综上所述，结构原理，模型研究和生物学活性表征表明，这种新型支架可以显着减弱宿主内HIV-1的复制，从而为开发新型抗HIV治疗候选物开辟了新视野。