Department of Molecular and Microbiology, National Center for Biodefense & Infectious Diseases, George Mason University, Manassas, VA 20110, USA.
Virology. 2011 Jun 20;415(1):56-68. doi: 10.1016/j.virol.2011.03.025. Epub 2011 Apr 22.
The HIV-1 protein Tat is a critical regulator of viral transcription and has also been implicated as a mediator of HIV-1 induced neurotoxicity. Here using a high throughput screening assay, we identified the GSK-3 inhibitor 6BIO, as a Tat-dependent HIV-1 transcriptional inhibitor. Its ability to inhibit HIV-1 transcription was confirmed in TZM-bl cells, with an IC(50) of 40nM. Through screening 6BIO derivatives, we identified 6BIOder, which has a lower IC(50) of 4nM in primary macrophages and 0.5nM in astrocytes infected with HIV-1. 6BIOder displayed an IC(50) value of 0.03nM through in vitro GSK-3β kinase inhibition assays. Finally, we demonstrated 6BIO and 6BIOder have neuroprotective effects on Tat induced cell death in rat mixed hippocampal cultures. Therefore 6BIO and its derivatives are unique compounds which, due to their complex mechanisms of action, are able to inhibit HIV-1 transcription as well as to protect against Tat induced neurotoxicity.
HIV-1 蛋白 Tat 是病毒转录的关键调节剂，也被认为是 HIV-1 诱导神经毒性的介质。在这里，我们使用高通量筛选测定法，鉴定出 GSK-3 抑制剂 6BIO 是一种依赖 Tat 的 HIV-1 转录抑制剂。在 TZM-bl 细胞中，其抑制 HIV-1 转录的能力得到了证实，IC（50）为 40nM。通过筛选 6BIO 衍生物，我们鉴定出 6BIOder，它在感染 HIV-1 的原代巨噬细胞中的 IC（50）为 4nM，在星形胶质细胞中的 IC（50）为 0.5nM。6BIOder 通过体外 GSK-3β 激酶抑制测定显示出 0.03nM 的 IC（50）值。最后，我们证明 6BIO 和 6BIOder 对 Tat 诱导的大鼠混合海马培养物中的细胞死亡具有神经保护作用。因此，6BIO 及其衍生物是独特的化合物，由于其复杂的作用机制，既能抑制 HIV-1 转录，又能防止 Tat 诱导的神经毒性。
