Identification of Anti-HIV Lead Compounds Targeting Rev

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。HIV病毒中的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至关重要的作用，在细胞质中它可以被翻译或包装。在初步工作中，针对HIV Rev蛋白的两种不同的检测方法确定了具有噻吩吡啶支架的结构相似的hit。这类化合物随后被证明能抑制HIV复制，并表现出低毒性。利用购买的类似物对噻吩吡啶类进行了扩展研究，发现了明确的结构-活性关系（SAR），表明了一个明确的分子靶点和通过化学优化进一步提高效力的潜力。在这里，我们建议对噻吩吡啶家族进行系统的结构-活性研究，使用合成的类似物，并采用强大的抗病毒，报告蛋白和ADME-Tox检测。对噻吩吡啶与购买的类似物的初步研究提供了有关吡啶环SAR的有用信息。然而，对这些化合物的综合评价和其中所含基本药效团的鉴定将需要化学合成。因此，我们计划进行多轮模拟合成和筛选，使新兴的SAR能够指导进一步的优化。这些研究的成功结论将看到一种或多种铅化学型的鉴定，从而使铅优化研究在后续工作阶段。公共卫生相关性：一种有前途的Rev抑制剂的结构-活性研究被提出。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类似药物的特性。

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.