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 毒性神经细胞。因此，我们认为靶向GPR31可能提供了一条治疗途径 一种安全有效的抗血小板治疗结合二次神经保护的研究进展 为缓解急性脑卒中的神经后遗症提供更有效和更安全的 纤溶治疗的替代选择或辅助治疗。我们最近成功地确定了第一个 有效的GPR31拮抗剂使用我们的细胞穿透、膜系留、胃泌素技术将成为 在这些临床前可行性研究中被证实为抗血小板和抗中风药物。我们在这里展示了 这种I3-环衍生的GPR31脂肽具有很强的抗血小板活性，几乎完全抑制 小鼠动脉血栓形成对止血无影响。GPR310肽的初步数据 表明载脂蛋白E-/-小鼠的动脉粥样硬化病变负担显著减少。此外，我们还提供 GPR310肽对急性脑损伤的HT22神经细胞具有直接神经保护作用的证据 谷氨酸介导的氧化应激。该项目第一阶段的目标是开发GPR310 Producin是绿洲制药公司(马萨诸塞州列克星敦)和塔夫茨医疗中心的合作成果 (马萨诸塞州波士顿)和阿罗拉(俄勒冈州波特兰)，这将提供关键的早期里程碑，以推进最初的 商业开发的第一个GPR31抑制剂作为一种双重抗血小板、抗中风药物。这种可行性 研究将通过实现以下主要里程碑来确定拟议方案的科学价值 卒中模型中6个月安全性和有效性的结束以及两个物种中PK/PD的相关性。

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 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 feasibility 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 indicates a significant reduction in atherosclerotic lesion burden in ApoE-/- mice. 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 I STTR project is to develop the GPR310 pepducin as a collaborative effort between Oasis Pharmaceuticals (Lexington, MA), Tufts Medical Center (Boston, MA) and Aronora (Portland, OR) that would provide key early milestones to advance the initial commercial development of the first GPR31 inhibitor as a dual antiplatelet, anti-stroke drug. This feasibility study would establish the scientific merit of the proposed program by accomplishing the major milestones at the end of the 6 months of safety and efficacy in a stroke model and PK/PD correlations in two species.