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：
Colleen M Brophy
金额：
$ 26.19万
依托单位：
VASAMETRIX LLC
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：
https://reporter.nih.gov/project-details/10384341
关键词：
Actins Affect Amino Acid Sequence Bathing Biological Assay Blood Blood Vessels Brain Bypass Cells Cerebrovascular Circulation Cerebrovascular system Cerebrum Cessation of life Clinic Clinical Clinical Pathways Clinical Trials Cyclic GMP Cyclic GMP-Dependent Protein Kinases Defect Disease Down-Regulation Elements Enzymes Evaluation Event Family Government Guanylate Cyclase Hypotension Impairment Injections Intracranial Aneurysm Investigation Lead Link Magnetic Resonance Imaging Medical Modeling Morbidity - disease rate Muscle Muscle relaxation phase Myosin ATPase Neurologic Deficit Neurons Nimodipine Nitric Oxide Nitric Oxide Donors Nitric Oxide Pathway Orphan Outcome Peptides Perfusion Persons Phase Phase II Clinical Trials Phosphopeptides Phosphoproteins Phosphorylation Site Phosphoserine Physiological Population Preparation Prevention approach Program Development Protein Kinase Proteins Rattus Refractory Regulation Risk Rupture Signal Pathway Signal Transduction Small Business Technology Transfer Research Solubility Stroke Subarachnoid Hemorrhage Survivors Tertiary Protein Structure Therapeutic Therapeutic Uses Tissues Toxic effect Translating Vascular Smooth Muscle Vasodilation Vasodilator Agents Vasospasm Work analog clinical efficacy depolymerization drug development functional outcomes hemodynamics improved in vivo inhibitor lead candidate mimetics mortality neurobehavior neurobehavioral novel peptide drug peptidomimetics pre-clinical preclinical study prevent protein activation radiological imaging rational design receptor response tat Protein treatment duration vasodilator-stimulated phosphoprotein young 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.

项目概要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缺血（中风）。总体发病率（严重神经功能缺损 10-20% 的幸存者）和死亡率（50%）很高，并且该疾病影响相对年轻的成年人人口。预防SAH后迟发性血管痉挛和神经缺血的治疗选择是目前仅限于血流动力学优化和尼莫地平，其临床疗效有限。因此，SAH 后迟发性血管痉挛的治疗代表了孤儿中未满足的临床需求。具有严重临床后果的人群。用现有的血管扩张剂治疗 SAH 引起的血管痉挛的尝试常常失败，因为全身性的原因低血压（导致脑灌注减少）和难治性脑血管系统激活一氧化氮 (NO) 依赖性信号通路。5 NO 信号调节血管平滑肌（VSM）松弛和脑血流调节。反应受损脑血管向血管扩张剂转变，即 SAH 后血管舒张受损，可能是由于下调 SAH 后 NO 通路中信号元件的研究。本次调查的假设是使用合理设计的下游效应器的细胞渗透性磷酸肽模拟物进行治疗 NO途径的蛋白质将绕过下调的信号元件，恢复血管舒张，并且预防 SAH 后迟发性血管痉挛。这种方法比激活或抑制受体或酶的方法。另外，这种做法特别对于 SAH 非常有用，其中预防全身性低血压和优化脑血管舒张是重要的最重要的。 cGMP 依赖性蛋白底物的细胞渗透性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经过合理设计并合成。三种候选肽被证明可以在体外直接松弛完整的 VSM 生物活性测定。序列最短、生物活性最强的肽（记为VP3）被选为用于确定体内功效的最佳肽。