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
- 来源:
- 关键词:AccelerationAcuteAdultAdverse effectsAlteplaseArachidonate 12-LipoxygenaseAreaBiological AssayBlood PlateletsBostonBrain EdemaCanis familiarisCardiovascular systemCause of DeathCell DeathCellsCentral Nervous SystemCerebrovascular DisordersChemistryClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCoagulation ProcessCoupledCytochrome P450DataDevelopmentDisabled PersonsDoseEnzyme InductionEnzyme InhibitionEnzymesFDA approvedFatty AcidsFormulationG-Protein-Coupled ReceptorsGPR31 receptorGTP-Binding ProteinsGeneticGlucoseGlutamatesGoalsGrantHemorrhageHemostatic functionHepaticHydroxyeicosatetraenoic AcidsHypertensionImplantIndividualInfarctionInflammationInflammatoryInfusion proceduresIntracranial HemorrhagesIntravenousIschemic StrokeKnockout MiceLipidsMediatingMedicalMedical centerMembraneMetabolismModelingMolecular TargetMusMutationNeurologicNeurologyNeuronsOrphanOxidative StressOxygenPapioPathologicPenetrationPharmaceutical PreparationsPharmacologic SubstancePharmacologyPharmacology StudyPhasePhase I Clinical TrialsPhenocopyPhysiologicalPrimary PreventionProductionProgram DevelopmentProstateRattusRecoveryReportingRisk FactorsRoleSafetySeriesSignal TransductionSignaling MoleculeSmall Business Technology Transfer ResearchSpecificityStrokeSymptomsTechnologyTelemetryTherapeuticThrombolytic TherapyThrombosisThrombotic StrokeTimeTissue ModelTissuesToxic effectToxicologyValidationWateracute strokeantagonistclinical effectcommercializationcost estimatedesigndisabilitydrug developmentefficacy evaluationexperimental studyfirst-in-humanimprovedinhibitormanufacturemeetingsmethod developmentmouse modelneuron lossneuroprotectionoxidationphase 1 studypost strokepre-clinicalprotective effectreceptorrespiratorysafety assessmentside effectstroke modelstroke patientstroke therapystroke victimsthrombotic
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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
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$ 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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