A small molecule screen to target viral RNA-protein complexes

描述（由申请人提供）：鉴于对现有药物方案具有耐药性的病毒的出现，迫切需要新的HIV治疗方法。rna -蛋白复合物是一种重要的、未被充分利用的药物靶点。在HIV中，Tat-TAR和Rev-RRE RNA-蛋白复合物分别在RNA转录和核输出中发挥重要作用。这些rna -蛋白复合物的破坏可以抑制病毒复制，因此这种策略对抗病毒药物的发现具有很大的希望。先进遗传系统公司（AGS）和加州大学旧金山分校联合开发了一种基于细胞的药物筛选平台，以靶向RNA和RNA-蛋白复合物。筛选平台通过对照抑制剂和4500个靶向Rev-RRE的小分子化合物进行了严格的评估。从这个筛选中，我们发现了特异性靶向Rev的新化合物，表现出低毒性，表现出良好的药代动力学特性，并在亚微摩尔ic50下抑制HIV复制。这一结果给了我们很大的信心，我们已经开发出一种高质量的、强大的筛选平台，能够识别病毒rna蛋白靶点的抑制剂。我们现在希望利用我们的筛查平台开展针对HIV Rev- RRE和Tat-TAR的扩大筛查。我们将筛选一个小分子多样性文库，以确定新的分子实体，这些分子实体可以形成新的抗hiv治疗药物类别的基础。

DESCRIPTION (provided by applicant): There is a significant need for novel HIV therapies given the emergence of viruses resistant to existing drug regimens. RNA-protein complexes represent an important and under utilized drug target. In HIV, the Tat-TAR and Rev-RRE RNA- protein complexes carry out essential roles in RNA transcription and nuclear export respectively. Disruption of these RNA-protein complexes can inhibit viral replication, thus this strategy holds great promise for antiviral drug discovery. Advanced Genetic Systems (AGS) and UCSF have jointly developed a cell- based drug-screening platform to target RNA and RNA-protein complexes. The screening platform was rigorously evaluated with control inhibitors and a pilot screen of 4500 small molecule compounds targeting Rev-RRE. From this screen, we identified novel compounds that specifically target Rev, exhibit low toxicity, display favorable pharmacokinetic properties, and inhibit HIV replication at sub-micromolar IC50s. This result has given us great confidence that we have developed a high-quality, robust screening platform capable of identifying inhibitors of viral RNA-protein targets. We now wish to use our screening platform to carry out expanded screens targeting HIV Rev- RRE and Tat-TAR. We will screen a small molecule diversity library to identify new molecular entities that could form the basis of new classes of anti-HIV therapeutics. PUBLIC HEALTH RELEVANCE: There is significant need to develop new classes of antiviral drugs to combat emerging viral diseases and resistance to older drugs. RNA-protein complexes represent an important and under utilized viral drug target. Disruption of an RNA-protein complex can inhibit viral replication, thus this strategy holds great promise for antiviral drug discovery.