ORALLY ACTIVE INHIBITOR OF POLY (ADP) RIBOSE SYNTETHASE

自由基相关的胰岛细胞破坏的细胞和分子机制尚不完全清楚。这种胰岛细胞死亡的药理调节可能为糖尿病的实验治疗提供新的途径。最近对分离的胰岛细胞和其他细胞类型的研究表明，免疫细胞介导的胰岛细胞攻击过程中产生的强效氧化剂过氧亚硝酸盐和过氧化氢可触发细胞内级联反应，最终导致细胞能量衰竭。过氧化氢和过氧亚硝酸盐引发的DNA链断裂被核酶聚核糖合成酶（PARS）的一个特定区域识别。这导致PARS激活，启动能量消耗低效率的修复周期，导致二核苷酸池耗竭，减缓糖酵解和线粒体呼吸速率，减少ATP合成。因此，PARS作为细胞能量崩溃导致细胞坏死的终端介质。我们的初步数据表明，在链脲佐菌素诱导的糖尿病大鼠模型中，用一种新型的、有效的PARS抑制剂对PARS进行药理学抑制可以减少高血糖的发生和胰岛细胞的破坏。该抑制剂在口服治疗方案中有效。除了药理学抑制剂的数据外，我们组和另外两个组以及另外两个组的研究人员的数据表明，PARS缺陷（敲除）小鼠对链脲佐菌素诱导的糖尿病具有抗性。由于链脲佐菌素模型不能完全预测人类的情况，目前方案的第一个目的是研究口服PARS抑制剂治疗对自发性自身免疫性糖尿病（NOD小鼠）发展的影响。拟议研究的第二个目的是进行标准的临床前研究，以开始表征口服PARS抑制剂的毒性和药效学。目前的提案将提供(1)关于自身免疫性糖尿病机制的新机制信息，(2)将产生数据，这将有助于我们公司制定新的，有效的，口服活性PARS抑制剂的临床前开发的战略决策。拟议的商业应用：在美国，一种安全有效的自身免疫性糖尿病治疗方法的市场价值估计为每年10亿美元。

The cellular and molecular mechanisms of free radical-related pancreatic islet cell destruction are incompletely understood. Pharmacological modulation of this islet cell death may provide novel avenues for the experimental therapy of diabetes. Recent studies in isolated islet cells, and other cell types demonstrate that peroxynitrite and hydrogen peroxide, potent oxidants produced during immune-cell mediated islet cell attack, trigger an intracellular cascade culminating in cellular energy failure. DNA strand-breakage triggered by hydrogen peroxide and peroxynitrite is recognized by a specific domain of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). This results in the activation of PARS which initiates an energy consuming inefficient repair cycle, with resultant depletion of dinucleotide pools, slowing the rate of glycolysis and mitrochondrial respiration, reducing ATP synthesis. Thus, PARS acts as a terminal mediator of cellular energetic collapse leading to cellular necrosis. Our preliminary data show that pharmacological inhibition of PARS with a novel, potent inhibitor of PARS reduces the development of hyperglycemia and islet cell destruction in a rat model of streptozotocin- induced diabetes. The inhibitor was effective in the oral treatment regimen. In addition to the data with pharmacological inhibitors, data from our group, and also from two other group, and also from two other groups of investigators demonstrate that PARS deficient (knockout) mice are resistant against streptozotocin-induced diabetes. Because of the streptozotocin-model is not fully predictable for the human situation, the first aim of the current protocol is aimed at investigating the effect of oral treatment with PARS inhibitor on the development of spontaneous autoimmune diabetes (NOD mice). The second aim of the proposed studies is to perform standard preclinical studies to begin to characterize the toxicity and pharmacodynamics of orally administered PARS inhibitor. The current proposal will provide (1) novel mechanistic information on the mechanism of autoimmune diabetes, and (2) will result in data which will help our company in making a strategic decision for the preclinical development of a novel, potent, orally active PARS inhibitors. PROPOSED COMMERCIAL APPLICATION: To market for a safe and effective therapy for autoimmune diabetes is estimated at > $1 billion in the US per annum.