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

脂质受体 GPR31 作为抗血栓和中风治疗的靶点

• 批准号: 10325956
• 负责人: Athan Kuliopulos
• 金额: $ 36.18万
• 依托单位: OASIS PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325956
• 关键词: Acute; Adult; Adverse effects; Alteplase; Animal Model; Apolipoprotein E; Apoptosis; Arachidonate 12-Lipoxygenase; Arachidonic Acids; Area; Arterial Fatty Streak; Atherosclerosis; Biological Availability; Blood Platelets; Boston; Brain Edema; Calcium; Cause of Death; Cell Death; Cells; Cerebrovascular Disorders; Coronary; Coupled; Data; Development; Diet; Disabled Persons; Dose; Enzymes; F2R gene; FDA approved; Fatty Acids; Feasibility Studies; Formulation; Free Radicals; G-Protein-Coupled Receptors; GPR31 receptor; GTP-Binding Proteins; Glucose; Glutamate Receptor; Glutamates; Goals; Hemorrhage; Hemostatic function; Human; Hydroxyeicosatetraenoic Acids; Hypertension; Infarction; Inflammation; Inflammatory; Intervention; Intracranial Hemorrhages; Ischemic Stroke; LOX gene; Lesion; Lipids; Mediating; Medical; Medical center; Membrane; Metabolism; Modeling; Molecular Target; Mus; Neurologic; Neurons; Oregon; Orphan; Oxidative Stress; Oxygen; Papio; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase II Clinical Trials; Physiological; Platelet Activation; Primary Prevention; Production; Prostate; Reporting; Risk Factors; Rodent; Role; Safety; Series; Signal Transduction; Signaling Molecule; Small Business Technology Transfer Research; Stroke; Symptoms; Technology; Testing; Therapeutic; Thrombolytic Therapy; Thrombosis; Thrombotic Stroke; Time; Tissues; Toxic effect; Toxicology; acute stroke; cost estimate; disability; in vivo; inhibitor/antagonist; ischemic injury; mouse model; neuron loss; neurotoxicity; nonhuman primate; oxidation; pharmacokinetics and pharmacodynamics; post stroke; pre-clinical; programs; protective effect; receptor; recruit; stroke model; stroke patient; stroke therapy; stroke victims; subcutaneous

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.

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 神经细胞毒性因此，我们提出，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， 减轻中风急性神经后遗症的效果，以提供更有效和更安全的 纤维蛋白溶解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GPR 31拮抗剂，使用我们的细胞穿透，膜系，Pepducin技术， 在这些临床前可行性研究中验证为抗血小板和抗中风药物。我们在这里展示 这种β 3环衍生的GPR 31脂肽具有有效的抗血小板活性，并且几乎完全抑制血小板聚集。 动脉血栓形成，对小鼠止血无影响。GPR 310肽蛋白的初步数据 表明ApoE-/-小鼠中动脉粥样硬化病变负荷的显著降低。此外，我们提供 GPR 310 pepducin对经受了以下处理的HT 22神经元细胞的直接神经保护作用的证据： 谷氨酸介导的氧化应激。第一阶段STTR项目的目标是开发GPR 310 pepducin是Oasis Pharmaceuticals（列克星敦，MA）、Tufts Medical Center （波士顿，马萨诸塞州）和Aronora（波特兰，OR），这将提供关键的早期里程碑，以推进最初的 第一个GPR 31抑制剂作为双重抗血小板、抗中风药物的商业开发。本可行性 研究将通过完成主要里程碑来确定拟议计划的科学价值， 卒中模型中6个月安全性和疗效结束时以及两个种属中的PK/PD相关性。