Development of a hepatoprotective strategy for preventing drug-induced liver inju

描述（由申请方提供）：药物诱导的肝毒性是急性肝损伤的最常见原因，急性肝损伤是一种潜在致死性疾病，目前的治疗仅限于支持性治疗和肝移植。这也是最常见的原因，可能挽救生命的药物在开发过程中被放弃，永远不会到达患者。海普罗泰克公司成立的目的是开发对肝脏安全的药物和药物性肝损伤的治疗方法。我们最近发现了间隙连接依赖性通讯在药物诱导的肝损伤传播中的新作用，并确定了干扰该途径的工具化合物。Heprotech现在寻求资金支持一项药物发现计划，该计划将使用小分子库的高通量筛选来开发一系列治疗化合物，这些化合物将作为一流的肝脏保护剂。该项目的总体目标是开发一种高通量筛选检测方法，该方法将识别一类新的药物， 治疗和预防药物性肝损伤。这项资助的重点是发现连接蛋白32（Cx32）的抑制剂，Cx32是一种肝脏特异性间隙连接蛋白，我们最近证明它对传播药物诱导的肝损伤至关重要。该项目的具体目标是：（1）发展 用于测量间隙连接渗透性的含Cx32的脂质体报告系统，2）使用Cx32脂质体报告系统建立可重复的高通量筛选测定，和3）筛选Cx32半通道的抑制剂并评价它们在基于活细胞的二次筛选中限制细胞损伤传播的能力。这一努力的预期成果是一系列有前途的强效Cx32抑制剂，这些抑制剂可以在SBIR计划的II期期间通过严格的临床前研究进一步开发。

DESCRIPTION (provided by applicant): Drug-induced hepatotoxicity is the most common cause of acute liver injury, a potentially fatal condition for which current therapies are limited o supportive care and liver transplantation. It is also the most common reason that potentially life-saving drugs are abandoned during development and never reach patients. Heprotech Inc. was formed to develop liver-safe pharmaceuticals and treatments for drug-induced liver injury. We recently discovered a novel role for gap junction-dependent communication in the propagation of drug-induced liver injury and have identified a tool compound that interferes with this pathway. Heprotech now seeks funding to support a drug discovery program that will use high throughput screening of small molecule libraries to develop a portfolio of therapeutic compounds that will serve as first-in-class hepatoprotectants. The overall goal of this project is to developa high throughput screening assay that will identify a novel class of drugs that will be developed to treat and prevent drug-induced liver injury. This grant focuses on discovery of inhibitors of connexin 32 (Cx32), a liver-specific gap junction protein that we recently demonstrated to be essential for propagating drug-induced liver injury. The project's specific aims are: 1) To develop a Cx32-containing liposome reporter system for measuring gap junction permeability, 2) To establish a reproducible high throughput screening assay using the Cx32 liposome reporter system, and 3) To screen for inhibitors of Cx32 hemichannels and evaluate their ability to limit propagation of cellular injury in a live cell-based secondary screen. The anticipated outcome of this effort is a collection of promising potent Cx32 inhibitors that can be further developed through rigorous preclinical studies during phase II of this SBIR program.