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。
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
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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
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9408141 - 财政年份:2013
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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:
8648560 - 财政年份:2013
- 资助金额:
$ 99.98万 - 项目类别:
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