Center for Sickle Cell Disease, 1840 7th Street, N.W. HURB1, Suite 202, Washington DC 20001. United States.
Curr Pharm Des. 2017;23(28):4122-4132. doi: 10.2174/1381612823666170704123620.
Despite efficient suppression of HIV-1 replication, current antiviral drugs are not able to eradicate HIV-1 infection. Permanent HIV-1 suppression or complete eradication requires novel biological approaches and therapeutic strategies. Our previous studies showed that HIV-1 transcription is regulated by host cell protein phosphatase-1. We also showed that HIV-1 transcription is sensitive to the reduction of intracellular iron that affects cell cycle-dependent kinase 2. We developed protein phosphatase 1-targeting small molecules that inhibited HIV-1 transcription. We also found an additional class of protein phosphatase-1-targeting molecules that activated HIV-1 transcription and reported HIV-1 inhibitory iron chelators and novel curcumin analogs that inhibit HIV-1. Here, we review HIV-1 transcription and replication with focus on its regulation by protein phosphatase 1 and cell cycle dependent kinase 2 and describe novel small molecules that can serve as future leads for anti-HIV drug development.
Our review describes in a non-exhaustive manner studies in which HIV-1 transcription and replication are targeted with small molecules. Previously, published studies show that HIV-1 can be inhibited with protein phosphatase-1-targeting and iron chelating compounds and curcumin analogs. These results are significant in light of the current efforts to eradicate HIV-1 through permanent inhibition. Also, HIV-1 activating compounds can be useful for "kick and kill" therapy in which the virus is reactivated prior to its inhibition by the combination antiretroviral therapy.
The studies described in our review point to protein phosphatase-1 as a new drug target, intracellular iron as subject for iron chelation and novel curcumin analogs that can be developed for novel HIV-1 transcription- targeting therapeutics.
尽管 HIV-1 复制得到了有效抑制，但现有的抗病毒药物仍无法彻底清除 HIV-1 感染。要实现 HIV-1 的永久抑制或彻底清除，需要新的生物学方法和治疗策略。我们之前的研究表明，HIV-1 的转录受到宿主细胞蛋白磷酸酶-1 的调控。我们还发现，HIV-1 的转录对细胞内铁的减少敏感，而铁的减少会影响细胞周期依赖性激酶 2。我们开发了针对蛋白磷酸酶-1 的小分子，这些小分子能够抑制 HIV-1 的转录。我们还发现了另一类靶向蛋白磷酸酶-1 的分子，它们能够激活 HIV-1 的转录，并报道了具有 HIV-1 抑制作用的铁螯合剂和新型姜黄素类似物，它们能够抑制 HIV-1。本文综述了 HIV-1 的转录和复制，重点关注蛋白磷酸酶-1 和细胞周期依赖性激酶 2 对其的调控，并描述了可作为未来抗 HIV 药物研发的新型小分子。
本文以非详尽的方式描述了使用小分子靶向 HIV-1 转录和复制的研究。之前的研究表明，HIV-1 可以被靶向蛋白磷酸酶-1 的化合物、铁螯合剂和姜黄素类似物抑制。这些结果对于通过永久抑制来消除 HIV-1 的当前努力具有重要意义。此外，HIV-1 激活化合物可用于“踢和杀”疗法，即在联合抗逆转录病毒疗法抑制病毒之前，先将其激活。
本文所述的研究表明，蛋白磷酸酶-1 是一个新的药物靶点，细胞内铁是铁螯合的目标，新型姜黄素类似物可用于开发新型靶向 HIV-1 转录的治疗方法。
