Lipid Receptor GPR31 as a Target for Anti-Thrombotic and Stroke Therapy

尽管抗血小板和抗脂质治疗的普遍使用，中风仍然是第三大死亡原因 是美国成人残疾的主要原因，估计花费在340亿美元左右 每年。每年795，000名中风患者中约有20%在一年内死亡，15-30%死于中风。 永久残疾。抗血小板治疗主要用于急性缺血性中风的一级预防， 脑血管疾病生物活性脂肪酸是一类新的分子靶点， 治疗潜力，因为它们作为调节代谢的信号分子的不同作用， 炎症12-LOX氧化花生四烯酸可产生多种生物活性物质， 脂质，包括代谢物12（S）-HETE。脂质受体GPR 31是一种孤儿A类GPCR，是一种12（S）- HETE受体最近被证明参与炎症信号传导。我们最近发现GPR 31 介导血小板中的12（S）-HETE促血栓形成信号传导，并促进谷氨酸诱导的氧化 神经细胞的毒性。因此，我们认为靶向GPR 31可能提供一种治疗途径， 开发一种安全有效的抗血小板治疗， 神经保护作用，以减轻中风的急性神经后遗症， 有效和更安全的替代选择或辅助纤维蛋白溶解治疗。我们最近成功地 使用我们的细胞穿透、膜系连的Pepducin鉴定第一个有效的GPR 31拮抗剂 在这些临床前IND使能研究中验证的技术作为抗血小板和抗卒中药物 剂我们在此表明，这种i3环衍生的GPR 31脂肽具有有效的抗血小板活性， 完全抑制小鼠动脉血栓形成而不影响止血。初步数据， GPR 310肽转运蛋白显示出与GPR 310肽转运蛋白类似的小鼠中风梗塞面积的高度显著减少。 Gpr 31缺陷的保护作用。此外，我们还提供了直接神经保护作用的证据， GPR 310 pepducin在经历谷氨酸介导的氧化应激的HT 22神经元细胞上的作用。目标 第2阶段STTR项目的目的是开发GPR 310 pepducin，作为Oasis与 Pharmaceuticals（列克星敦，MA），Tufts Medical Center（波士顿，MA），将提供稳健的IND数据 推进第一个GPR 31抑制剂作为双重抑制剂的初步商业开发所需的一揽子计划 抗血小板抗中风药这项药物开发计划将建立的科学价值， 通过在2年GLP安全性/药理学研究结束时完成主要里程碑实现GPR 31目标 以及卒中模型±溶栓治疗的疗效，以支持I期首次人体临床试验。

Despite prevalent use of anti-platelet and anti-lipid therapies, stroke remains the third major cause of death and is the leading cause of adult disability in the US with an estimated cost in the range of $34 billion annually. Approximately 20% of the annual 795,000 stroke patients die within one year and 15-30% are permanently disabled. Antiplatelet therapy is mainly used for primary prevention of acute ischemic stroke in cerebrovascular disease. Bioactive fatty acids are a new class of molecular targets that hold great therapeutic potential because of their diverse role as signaling molecules that regulate metabolism and inflammation. The oxidation of arachidonic acid by 12-LOX results in the production of a number of bioactive lipids including the metabolite 12(S)-HETE. The lipid receptor GPR31, an orphan class A GPCR, is a 12(S)- HETE receptor recently shown to be involved in inflammatory signaling. We recently discovered that GPR31 mediates 12(S)-HETE prothrombotic signaling in platelets and promotes glutamate-induced oxidative toxicity in neuronal cells. Therefore, we propose that targeting GPR31 may provide a therapeutic path towards development of a safe and effective antiplatelet therapy that is coupled with secondary neuroprotective effects for mitigating against the acute neurologic sequela of stroke to provide a more effective and safer alternative option or adjunct to fibrinolytic therapy. We have recently succeeded in identifying the first effective GPR31 antagonist using our cell-penetrating, membrane-tethered, Pepducin technology to be validated in these preclinical IND-enabling studies as an anti-platelet and anti-stroke agent. We show here that this i3-loop derived GPR31 lipopeptide has potent antiplatelet activity and nearly completely suppresses arterial thrombosis without an effect on hemostasis in mice. Preliminary data with the GPR310 pepducin shows a highly significant reduction in stroke infarct area in mice similar to the protective effect of Gpr31-deficiency. Furthermore, we provide evidence for a direct neuroprotective effect of the GPR310 pepducin on HT22 neuronal cells subjected to glutamate mediated oxidative stress. The goal of this Phase 2 STTR project is to develop the GPR310 pepducin as a collaborative effort between Oasis Pharmaceuticals (Lexington, MA), Tufts Medical Center (Boston, MA) that would provide a robust IND data package required to advance the initial commercial development of the first GPR31 inhibitor as a dual antiplatelet, anti-stroke drug. This drug development program would establish the scientific merit of the GPR31 target by accomplishing the major milestones at the end of 2 years of GLP safety/pharmacology and efficacy in stroke models ± thrombolytic therapy to support a Phase I first-in-human clinical trial.