Identification of Anti-HIV Lead Compounds Targeting Rev

描述（由申请人提供）：鉴于出现了对现有药物方案具有耐药性的病毒，因此对新型HIV疗法存在重大需求。HIV中的Rev-RRE蛋白-RNA相互作用在病毒mRNA从细胞核转运到细胞质中起着重要作用，在细胞质中可以翻译或包装。在初步工作中，针对HIV Rev蛋白的两种不同的测定鉴定了具有噻吩并吡啶骨架的结构相似的命中物。这类化合物随后显示出抑制HIV复制并表现出低毒性。使用购买的类似物对噻吩并吡啶类进行的扩展研究显示了明确的结构-活性关系（SAR），表明了明确的分子靶标和通过化学优化进一步提高效力的潜力。在这里，我们建议进行系统的结构活性研究的噻吩并吡啶家族使用合成的类似物，并采用一个强大的面板的抗病毒，报告，和ADME-Tox测定。噻吩并吡啶与购买的类似物的初步研究提供了有用的信息，关于吡啶环SAR。然而，这些化合物的综合评价和嵌入其中的基本药效团的识别将需要化学合成。因此，我们计划进行多轮模拟合成和筛选，允许新兴SAR指导进一步优化。这些研究的成功结论将看到一个或多个铅化学型的鉴定，从而使铅优化研究在后续阶段的工作。公共卫生相关性：描述了一种有前途的Rev抑制剂的拟议结构-活性研究。新的类似物将被合成或从供应商处采购，然后测试其抗病毒活性和药物样特性。

DESCRIPTION (provided by applicant): There is a significant need for novel HIV therapies given the emergence of viruses resistant to existing drug regimens. The Rev-RRE protein-RNA interaction in HIV plays an essential role in the transport of viral mRNA from the nucleus to the cytoplasm where it can be translated or packaged. In preliminary work, two distinct assays targeting the HIV Rev protein identified structurally similar hits possessing a thienopyridine scaffold. Compounds of this class were subsequently shown to inhibit HIV replication and to exhibit low toxicity. An expanded study of the thienopyridine class using purchased analogs revealed clear structure-activity relationships (SAR), suggesting a well-defined molecular target and the potential for further improvement in potency through chemical optimization. Here, we propose to conduct a systematic structure-activity study of the thienopyridine family using synthesized analogs and employing a robust panel of antiviral, reporter, and ADME-Tox assays. The initial study of thienopyridines with purchased analogs provided useful information concerning pyridine ring SAR. However, a comprehensive evaluation of these compounds and the identification of the essential pharmacophore imbedded within them will require chemical synthesis. Thus, we plan to perform multiple rounds of analog synthesis and screening, allowing emerging SAR to guide further optimization. The successful conclusion of these studies will see the identification of one or more lead chemotypes, thus enabling lead optimization studies in a subsequent phase of work. PUBLIC HEALTH RELEVANCE: A proposed structure-activity study of a promising Rev inhibitor is described. New analogs will be synthesized or procured from vendors and then tested for antiviral activity and drug-like properties.