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

基本信息

  • 批准号:
    10603440
  • 负责人:
  • 金额:
    $ 99.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

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.
尽管普遍使用抗血小板和抗脂质疗法,中风仍然是第三大死亡原因 是美国成人残疾的主要原因,估计造成的损失达 340 亿美元 每年。每年 795,000 名中风患者中,约有 20% 在一年内死亡,其中 15-30% 死于中风。 永久禁用。抗血小板治疗主要用于急性缺血性脑卒中的一级预防 脑血管疾病。生物活性脂肪酸是一类新的分子靶标,具有很大的用途 由于它们作为调节代谢和代谢的信号分子的多种作用,具有治疗潜力 炎。 12-LOX 氧化花生四烯酸会产生许多生物活性物质 脂质,包括代谢物 12(S)-HETE。脂质受体 GPR31 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 GPR31 介导血小板中的 12(S)-HETE 血栓前信号传导并促进谷氨酸诱导的氧化 对神经细胞的毒性。因此,我们提出靶向GPR31可能提供一条治疗途径 致力于开发一种安全有效的抗血小板治疗,并与二次治疗相结合 减轻中风急性神经系统后遗症的神经保护作用,提供更多 有效且更安全的替代选择或纤溶治疗的辅助疗法。我们最近成功地 使用我们的细胞穿透性膜束缚 Pepducin 鉴定第一个有效的 GPR31 拮抗剂 该技术将在这些临床前 IND 研究中作为抗血小板和抗中风药物进行验证 代理人。我们在此表明​​,这种 i3 环衍生的 GPR31 脂肽具有有效的抗血小板活性,并且几乎 完全抑制动脉血栓形成,且不影响小鼠的止血效果。初步数据与 GPR310 pepducin 显示小鼠中风梗塞面积的显着减少,与 Gpr31 缺陷的保护作用。此外,我们提供了直接神经保护作用的证据 HT22 神经元细胞上的 GPR310 pepducin 受到谷氨酸介导的氧化应激。目标 该 STTR 项目第 2 阶段的目标是开发 GPR310 pepducin,作为 Oasis 和 Oasis 之间的合作 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)将提供可靠的 IND 数据 推进第一个 GPR31 抑制剂作为双药的初步商业开发所需的软件包 抗血小板、抗中风药物。该药物开发计划将确立该药物的科学价值 GPR31 目标是在 GLP 安全性/药理学 2 年后完成主要里程碑 和中风模型的疗效±溶栓治疗,以支持 I 期首次人体临床试验。

项目成果

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Athan Kuliopulos其他文献

Athan Kuliopulos的其他文献

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{{ truncateString('Athan Kuliopulos', 18)}}的其他基金

Development of liver homing PAR2 pepducins for the treatment of Hepatocellular Carcinoma
开发肝归巢 PAR2 pepducins 用于治疗肝细胞癌
  • 批准号:
    10547111
  • 财政年份:
    2022
  • 资助金额:
    $ 99.98万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 99.98万
  • 项目类别:
PAR2 Pepducins as a Novel Treatment of Idiopathic Pulmonary Fibrosis
PAR2 Pepducins 作为特发性肺纤维化的新型治疗方法
  • 批准号:
    9906265
  • 财政年份:
    2018
  • 资助金额:
    $ 99.98万
  • 项目类别:
Development of PAR4 Pepducins as a Novel Antithrombotic Treatment
开发 PAR4 Pepducins 作为新型抗血栓治疗方法
  • 批准号:
    9254228
  • 财政年份:
    2017
  • 资助金额:
    $ 99.98万
  • 项目类别:
Development of PAR2 Inhibitors for the Treatment of Nonalcoholic steatohepatitis
开发用于治疗非酒精性脂肪性肝炎的 PAR2 抑制剂
  • 批准号:
    8781807
  • 财政年份:
    2014
  • 资助金额:
    $ 99.98万
  • 项目类别:
Development of PAR2 Pepducins as a Novel NASH Treatment
开发 PAR2 Pepducins 作为一种新型 NASH 治疗方法
  • 批准号:
    9408141
  • 财政年份:
    2013
  • 资助金额:
    $ 99.98万
  • 项目类别:
Development of PAR2 Inhibitors for the Treatment of Nonalcoholic steatohepatitis
开发用于治疗非酒精性脂肪性肝炎的 PAR2 抑制剂
  • 批准号:
    8648560
  • 财政年份:
    2013
  • 资助金额:
    $ 99.98万
  • 项目类别:

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