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

尽管普遍使用抗血小板和抗血脂治疗，中风仍然是第三大主要死亡原因。 它是美国成年人残疾的主要原因，估计成本在340亿美元左右 每年一次。每年795,000名中风患者中约有20%在一年内死亡，15%-30% 永久失能。抗血小板治疗主要用于急性缺血性卒中的一级预防。 脑血管疾病。生物活性脂肪酸是一类新的分子靶标 治疗潜力因为它们作为信号分子的不同作用，调节新陈代谢和 发炎。花生四烯酸被12-LOX氧化产生许多生物活性物质 脂类包括代谢物12(S)-HETE。脂质受体GPR31是一种孤儿A类gpr，是一个12(S)- HETE受体最近被发现参与炎症信号的传递。我们最近发现GPR31 介导12(S)-异丙基异丙基醚促血栓前信号转导并促进谷氨酸诱导的氧化 对神经细胞的毒性。因此，我们认为靶向GPR31可能提供了一条治疗途径 开发一种安全有效的抗血小板疗法，并结合继发性 神经保护作用为缓解中风的急性神经后遗症提供了更多 有效和安全的纤溶治疗的替代选择或辅助治疗。我们最近成功地做到了 使用我们的细胞穿透性、膜系留、胃泌素鉴定第一个有效的GPR31拮抗剂 作为抗血小板和抗中风的技术将在这些临床前启用IND的研究中得到验证 探员。我们在这里表明，这种来自I3-环的GPR31脂肽具有很强的抗血小板活性，几乎 完全抑制小鼠动脉血栓形成而不影响止血。初步数据： GPR310肽蛋白显示非常显著地减少了小鼠的中风梗死面积，类似于 GPR31缺乏症的保护作用此外，我们还提供了直接神经保护作用的证据。 谷氨酸介导的氧化应激对HT22神经细胞GPR310肽的影响目标是 该第二阶段STTR项目的目的是开发GPR310肽，作为OASIS之间的合作努力 制药公司(马萨诸塞州列克星敦)、塔夫茨医疗中心(马萨诸塞州波士顿)将提供强大的IND数据 推进首个GPR31双用途抑制剂初步商业化开发所需的一揽子计划 抗血小板、抗中风药物。这一药物开发计划将确立 在GLP安全性/药理学两年结束时完成主要里程碑的GPR31目标 在中风模型中的有效性±溶栓治疗，以支持第一阶段的人类临床试验。

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.