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

项目摘要 HBV X蛋白（HBx）代表了药物发现工作的一个有吸引力的靶点，因为它在以下方面起着核心作用： 激活病毒基因表达并促进允许HBV cccDNA形式持续存在的条件， 慢性感染个体的肝细胞。第一阶段SBIR可行性研究的目的是确定 选择性抑制HBx和宿主因子DDB1（UV）之间的关键相互作用的药物样化合物 损伤的DNA结合蛋白1），负责激活cccDNA模板的转录。 在第一阶段的资助期间，我们将对一个图书馆进行一次点击发现活动， 200，000种具有最佳药物特性的化合物。检测中出现的质量命中将受到 进行后续检测，研究效价、选择性和作用机制。最有趣的 这些化合物中的一种将接受药物化学驱动的直接接触来探索结构活性 关系（SAR）。该项目的总体目标是发现一个或多个新颖的铅系列， 定义为一种化学型抑制剂，表现出易处理的SAR、针对HBV的强效抗病毒活性， 细胞毒性极小。这些努力的成功将触发提交第二阶段申请， 将计划从早期潜在客户优化推进到候选人选择。

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.