Discovery of inhibitors that target HBx for the treatment of chronic HBV infection

项目总结 HBX蛋白(HBX)是药物发现工作的一个有吸引力的靶点，因为它在 激活病毒基因表达和促进条件，使cccDNA形式的乙肝病毒持续存在 慢性感染者的肝细胞。这项第一阶段SBIR可行性研究的目标是确定 选择性抑制HBx和宿主因子DDB1(UV)之间关键相互作用的类药物化合物 损伤的DNA结合蛋白1)，负责激活cccDNA模板的转录。 在此第一阶段资助期内，我们将针对 20万种具有最佳类药物性能的化合物。从化验中产生的高质量命中将受到 进行后续测试，以调查作用的效力、选择性和机制。最有趣的 其中的化合物将受到药物化学的驱动，以探索结构活性 关系(SAR)。该项目总体目标是发现一个或多个新的前导系列，这是 定义为一种化学型抑制物，显示出易处理的SAR，对乙肝病毒和 最小的细胞毒性。这些努力的成功将触发第二阶段申请的提交，这将 将计划从早期的潜在客户优化推进到候选人的选择。

PROJECT SUMMARY The HBV X protein (HBx) represents an attractive target for drug discovery efforts as it plays a central role in activating viral gene expression and promoting conditions that allow the cccDNA form of HBV to persist in the hepatocytes of chronically infected individuals. The objective of this Phase I SBIR feasibility study is to identify drug-like compounds that selectively inhibit a key interaction between HBx and a host factor DDB1 (UV damaged DNA binding protein 1) that is responsible for activating transcription from the cccDNA template. During the course of this Phase I funding period, we will execute a hit finding campaign against a library of 200,000 compounds with optimal drug-like properties. Quality hits that emerge from the assay will be subjected to follow-on testing that will investigate the potency, selectivity, and mechanism of action. The most interesting of these compounds will be subjected to medicinal chemistry driven hit-to-lead to explore structure-activity relationships (SAR). The overall goal of this project is to discover one or more novel lead series which is defined as a chemotype inhibitor that demonstrates tractable SAR, potent antiviral activity against HBV and minimal cytotoxicity. Success in these endeavors will trigger the submission of a Phase II application that will advance the program from Early Lead Optimization through to Candidate Selection.