ORALLY ACTIVE INHIBITOR OF POLY (ADP) RIBOSE SYNTETHASE

与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。对这种胰岛细胞死亡的药理调节可能为糖尿病的实验性治疗提供新的途径。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过氧亚硝酸盐和过氧化氢，会触发细胞内的级联反应，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链断裂是由核酶多(ADP-核糖)合成酶(PARS)的特定结构域识别的。这会导致PARs的激活，从而启动一个耗能的低效修复周期，从而导致二核苷酸池的耗尽，减缓糖酵解和线粒体呼吸的速度，减少ATP的合成。因此，PARS是导致细胞坏死的细胞能量崩溃的终末介质。我们的初步数据显示，在链脲佐菌素诱导的糖尿病大鼠模型中，用一种新的、有效的PARS抑制剂抑制PARS可以减少高血糖和胰岛细胞破坏的发展。该抑制剂在口服治疗方案中有效。除了药物抑制剂的数据外，来自我们小组和另外两个小组以及另外两个研究小组的数据表明，PARS缺陷(基因敲除)小鼠对链脲佐菌素诱导的糖尿病具有抵抗力。由于链脲佐菌素模型不能完全预测人类的情况，当前方案的第一个目的是研究口服PARS抑制剂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标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发病机制的新的机制信息，以及(2)将产生的数据将帮助我们公司为新的、有效的、口服活性的PARS抑制剂的临床前开发做出战略决策。拟议的商业应用：在美国，每年向市场推介一种安全有效的自身免疫性糖尿病疗法的费用估计为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.