Virology studies of a small molecule HIV Rev inhibitor

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。先前，我们通过靶向HIV rev确定了抑制HIV复制的噻吩吡啶支架。我们使用商业和合成的类似物（总共bbb200）进行了广泛的结构-活性（SAR）研究，并确定了活性所需的关键结构元件（即基本药效团）。经过一轮又一轮的抗hiv和毒性测试的反复合成和测试，产生了可申请专利的新类似物，比我们最初的筛选结果强100倍，治疗指数达到4000，超过了我们最初的目标。在成功完成了向试验性新药（IND）提交的关键里程碑之后，潜在的公司合作伙伴要求我们进行病毒学实验，以充分表征不同病毒分离物和细胞类型的分子活性，并与当前批准的药物结合使用。

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. Previously we identified the thienopyridine scaffold that inhibited HIV replication and by targeting HIV Rev. We carried out extensive structure-activity (SAR) studies employing both commercial and synthesized analogs (> 200 total) and identified the key structural elements necessary for activity (i.e., the essential pharmacophore). Iterative rounds of synthesis and testing in a robust panel of anti-HIV and toxicity assays, produced patentable new analogs that are 100-fold more potent than our original screening hits and with therapeutic indices >4000, exceeding our original goals. Having successfully completed key milestones towards submission of an Investigational New Drug (IND), potential corporate partners have requested that we perform virology experiments to fully characterize the activity of the molecules with a diverse panel of viral isolates and cell types, and in combination with currently approved drugs.