Cell permeant peptidomimetics to prevent delayed vasospasm and neurological deficits after subarachnoid hemorrhage
细胞渗透性肽模拟物可预防蛛网膜下腔出血后迟发性血管痉挛和神经功能缺损
基本信息
- 批准号:10384341
- 负责人:
- 金额:$ 26.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2023-09-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAffectAmino Acid SequenceBathingBiological AssayBloodBlood VesselsBrainBypassCellsCerebrovascular CirculationCerebrovascular systemCerebrumCessation of lifeClinicClinicalClinical PathwaysClinical TrialsCyclic GMPCyclic GMP-Dependent Protein KinasesDefectDiseaseDown-RegulationElementsEnzymesEvaluationEventFamilyGovernmentGuanylate CyclaseHypotensionImpairmentInjectionsIntracranial AneurysmInvestigationLeadLinkMagnetic Resonance ImagingMedicalModelingMorbidity - disease rateMuscleMuscle relaxation phaseMyosin ATPaseNeurologic DeficitNeuronsNimodipineNitric OxideNitric Oxide DonorsNitric Oxide PathwayOrphanOutcomePeptidesPerfusionPersonsPhasePhase II Clinical TrialsPhosphopeptidesPhosphoproteinsPhosphorylation SitePhosphoserinePhysiologicalPopulationPreparationPrevention approachProgram DevelopmentProtein KinaseProteinsRattusRefractoryRegulationRiskRuptureSignal PathwaySignal TransductionSmall Business Technology Transfer ResearchSolubilityStrokeSubarachnoid HemorrhageSurvivorsTertiary Protein StructureTherapeuticTherapeutic UsesTissuesToxic effectTranslatingVascular Smooth MuscleVasodilationVasodilator AgentsVasospasmWorkanalogclinical efficacydepolymerizationdrug developmentfunctional outcomeshemodynamicsimprovedin vivoinhibitorlead candidatemimeticsmortalityneurobehaviorneurobehavioralnovelpeptide drugpeptidomimeticspre-clinicalpreclinical studypreventprotein activationradiological imagingrational designreceptorresponsetat Proteintreatment durationvasodilator-stimulated phosphoproteinyoung adult
项目摘要
PROJECT SUMMARY
Subarachnoid hemorrhage (SAH) due to rupture of an intracranial aneurysm leads to delayed
vasospasm resulting in neuroischemia (stroke). The overall morbidity (profound neurologic deficit in
10-20% of survivors) and mortality (50%) are high, and the disease affects a relatively young adult
population. Therapeutic options to prevent delayed vasospasm and neuroischemia after SAH are
currently limited to hemodynamic optimization and nimodipine, which have marginal clinical efficacy.
Thus, treatment of delayed vasospasm after SAH represents an unmet clinical need in an orphan
population with severe clinical consequences.
Attempts to treat SAH-induced vasospasm with existing vasodilators often fail because of systemic
hypotension (leading to decreased cerebral perfusion) and a cerebral vasculature that is refractory to
activation of nitric oxide (NO)-dependent signaling pathways.5 NO signaling modulates vascular
smooth muscle (VSM) relaxation and regulation of cerebral blood flow. The impaired response of
cerebral vessels to vasodilators, i.e. impaired vasorelaxation after SAH, is likely due to down regulation
of the signaling elements in the NO pathway after SAH. The hypothesis of this investigation is that
treatment with a rationally designed, cell permeant phosphopeptide mimetic of a downstream effector
protein of the NO pathway will bypass downregulated signaling elements, restore vasorelaxation, and
prevent delayed vasospasm after SAH. This approach is more targeted and stoichiometric than
approaches that activate or inhibit receptors or enzymes. In addition, this approach is particularly
useful in SAH where preventing systemic hypotension and optimizing cerebral vasodilation is
paramount.
A family of cell permeant phosphopeptide analogues of a substrate of cGMP-dependent Protein
Kinase (PKG), and an actin-associated protein that modulates VSM relaxation, were rationally designed
and synthesized. Three candidate peptides were demonstrated to directly relax intact VSM in ex vivo
bioactivity assays. The peptide with the shortest sequence (denoted as VP3) and strongest bioactivity
was chosen as the optimal peptide for use to determine in vivo efficacy.
项目摘要
由于颅内动脉瘤破裂导致蛛网膜下腔出血(SAH)导致延迟
血管痉挛导致神经化学(中风)。总体发病率(深刻的神经科缺陷
10-20%的幸存者)和死亡率(50%)很高,这种疾病影响了一个相对年轻的成年人
人口。 SAH后防止血管痉挛和神经性延迟的治疗选择是
目前仅限于具有边际临床功效的血液动力学优化和氮氨基胺。
因此,SAH后延迟血管痉挛的处理代表了孤儿的未满足的临床需求
人口严重临床后果。
试图用现有的血管扩张剂治疗SAH诱导的血管痉挛通常是由于系统性的
低血压(导致脑灌注降低)和脑脉管系统,难以耐受性
一氧化氮(NO)依赖性信号通路的激活。5NO信号传导调节血管
平滑肌(VSM)松弛和大脑血流的调节。反应受损
血管扩张剂的脑血管,即SAH后的血管延缓受损,可能是由于调节而导致的
SAH后NO途径中的信号元素。这项调查的假设是
用合理设计的细胞渗透磷酸肽模仿下游效应子的处理
NO途径的蛋白质将绕过下调的信号传导元件,恢复血管汇总和
SAH后防止血管痉挛延迟。这种方法比较有针对性和化学计量
激活或抑制受体或酶的方法。此外,这种方法尤其是
在防止系统性低血压和优化脑血管舒张的SAH中有用
最重要的。
CGMP依赖性蛋白的底物的细胞渗透磷酸肽类似物家族
激酶(PKG)和调节VSM松弛的肌动蛋白相关蛋白是合理设计的
并合成。证明了三种候选肽直接放松离体中的完整VSM
生物活性测定。最短序列(表示为VP3)和最强生物活性的肽
选择作为用于确定体内功效的最佳肽。
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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Colleen M Brophy其他文献
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