Novel Peptide for Dynamic Regulation of Lung Endothelium NOS/cGMP Functions

动态调节肺内皮 NOS/cGMP 功能的新型肽

• 批准号: 7742992
• 负责人: JAWAHARLAL M. PATEL
• 金额: $ 31.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742992
• 关键词: Amino Acids; Animal Model; Biochemical; Biological Availability; Blood Vessels; Clinical; Data; Dissociation; Dose; Endothelium; Event; Failure; Guanosine; Histologic; Hydrolysis; Lung; Mediating; Modeling; Molecular; Morbidity - disease rate; Nitric Oxide; Obstruction; Patients; Peptides; Perfusion; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Production; Pulmonary Circulation; Pulmonary Vascular Resistance; Pulmonary artery structure; Regimen; Regulation; Reporting; Role; Signal Transduction; Testing; Therapeutic; Vasodilation; Ventricular; base; caveolin 1; design; hemodynamics; human NOS3 protein; improved; inhibitor/antagonist; mortality; novel; novel therapeutic intervention; novel therapeutics; phosphoric diester hydrolase; pre-clinical; pulmonary arterial hypertension; pulmonary artery endothelial cell; response; synthetic peptide; treatment strategy; vasoconstriction

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is characterized by vascular obstruction and variable presence of vasoconstriction, leading to increased pulmonary vascular resistance and right ventricular failure. Despite its profound clinical consequences with high morbidity and mortality, therapeutic advances over the past 20 years have modestly improved survival of PAH patients. The combined use of available drugs to maximize the clinical benefit is an emerging strategy for the treatment of PAH. Pulmonary vascular endothelial nitric oxide (NO) synthase (eNOS)- derived NO is the major stimulant of cyclic guanosine 5' monophosphate (cGMP) production and NO/cGMP-dependent vasorelaxation in the pulmonary circulation. Alternatively, pulmonary vascular cGMP levels can also be elevated via inhibition of phosphodiesterase type 5 (PDE5) to achieve a similar response. We recently reported that an eleven amino acid (SSWRRKRKESS) synthetic peptide (P1) stimulates the catalytic activity of eNOS and causes NO/cGMP-dependent sustained vasorelaxation in isolated pulmonary artery (PA) segments and in lung perfusion models. More recent preliminary data suggest that P1 stimulation increases intracellular NO release and inhibits cGMP-specific PDE5 in pulmonary artery endothelial cells. Based on our earlier report and preliminary studies we hypothesize that P1 treatment with its unique dual action as a NO-releasing PDE5 inhibitor can be used as a novel therapeutic approach for the treatment of PAH. To test this hypothesis, the present study is designed to: 1) develop a physiologically relevant preclinical animal model of PAH with specific focus on assessment of bioavailability, dosing regimen, and efficacy of P1 therapy on the hemodynamic, histologic, and biochemical changes, and 2) identify the specific molecular events associated with P1-mediated caveolin-1/eNOS dissociation and activation of eNOS as well as the effects of P1 on PDE5 activity and cGMP hydrolysis. We anticipate that confirmation of mechanism-based dual action of this novel therapeutic peptide in a preclinical animal model will facilitate Phase I clinical trials for P1 treatment of PAH.

描述（由申请人提供）：肺动脉高压（PAH）的特征是血管阻塞和血管收缩的可变存在，导致肺血管阻力增加和右心室衰竭。尽管其具有严重的临床后果，发病率和死亡率较高，但过去20年的治疗进展已适度改善PAH患者的生存率。联合使用现有药物以最大化临床获益是PAH治疗的一种新兴策略。肺血管内皮一氧化氮合酶（eNOS）源性NO是肺循环中环鸟苷酸（cGMP）产生和NO/cGMP依赖性血管舒张的主要刺激物。或者，肺血管cGMP水平也可以通过抑制磷酸二酯酶5（PDE 5）来提高，以实现类似的反应。我们最近报道了一个11个氨基酸（SSWRRKRKESS）的合成肽（P1）在离体肺动脉（PA）节段和肺灌注模型中刺激eNOS的催化活性并引起NO/cGMP依赖性的持续血管舒张。最近的初步数据表明，P1刺激增加细胞内NO的释放，并抑制cGMP特异性PDE 5在肺动脉内皮细胞。基于我们早期的报告和初步研究，我们假设P1治疗具有独特的双重作用，作为NO释放PDE 5抑制剂，可用作治疗PAH的新治疗方法。为了验证这一假设，本研究旨在：1）开发生理学相关的PAH临床前动物模型，重点评估生物利用度、给药方案和P1治疗对血流动力学、组织学和生化变化的疗效，和2）鉴定与P1介导的小窝蛋白-1/eNOS的解离和激活以及P1对PDE 5活性和cGMP水解的影响。我们预计，在临床前动物模型中确认这种新型治疗肽的基于机制的双重作用将促进PAH P1治疗的I期临床试验。