Bi-Functional Peptides to Block Vasodilation and Vascular Leakage in Sepsis

双功能肽可阻断脓毒症中的血管舒张和血管渗漏

基本信息

批准号：
9408431
负责人：
Pierre Riviere
金额：
$ 29.81万
依托单位：
PEPTIDE LOGIC, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9408431
关键词：
ANGPT1 gene AVPR2 gene Agonist Angiopoietin-2 Animal Model Antibiotics Arteries Biological Assay Blood Blood Pressure Blood Vessels Blood flow Body Fluids Bradykinin Cardiovascular system Catheters Cephalic Cessation of life Chemicals Chemistry Clinical Complex Computer software Control Groups Data Developing Countries Disease Dose Edema Ensure Enzyme-Linked Immunosorbent Assay Evans blue stain Extravasation Fluid overload Freeze Drying Functional disorder Heart High Pressure Liquid Chromatography Hospital Costs Human Human Cloning Immune response In Vitro Infusion procedures Institutes Kidney Label Lead Length Life Link Liquid substance Liver Lung Measures Mesenteric Arteries Mesentery Modeling Molecular Conformation Molecular Target Monitor Mono-S Multiple Organ Failure Nature Organ Organ Weight Organ failure Pathogenicity Pathway interactions Patients Pentas Peptide Synthesis Peptides Perfusion Pharmaceutical Preparations Pharmacology Phase Plant Roots Plasma Plasma Albumin Polyethylene Glycols Positioning Attribute Property Rattus Recruitment Activity Reproducibility Research Resuscitation Risk Rodent Sepsis Septic Shock Site Small Business Innovation Research Grant Solid Spectrum Analysis Structure-Activity Relationship Time Tissues V1a vasopressin receptor Vascular resistance Vasoconstrictor Agents Vasodilation Water Work abdominal aorta analog beta-arrestin clinical candidate design in vivo liquid chromatography mass spectrometry mortality novel therapeutics pharmacophore preclinical development pressure programs response screening success treatment group vascular bed

项目摘要

PROJECT SUMMARY Sepsis is one of the most common life-threatening illness, leading to high mortality rates in both developed and developing countries.1 In the US alone, sepsis afflicted 1 to 3 million patients, caused 250,000 to 375,000 deaths in 2009,2 and accounted for $20.3 billion of US hospital costs in 2011.3 Besides the complex, redundant and often variable immunological responses,4 sepsis is always characterized by vasodilation and vascular leakage (VL),5-7 two constant, independent and complementary downstream cardiovascular pathogenic features directly responsible for decreased organ perfusion, tissue edema, organ dysfunction, multiple organ failure, and death. Today, sepsis patients are initially treated with antibiotics and given resuscitation fluids to maintain arterial blood pressure (ABP). Fluids are however purely symptomatic and do not address the root causes for decreased organ perfusion and function. Most concerning, they often lead to fluid overload,8 thereby further increasing tissue edema, organ failure, and mortality.9-12 Once fluids are no longer able to sustain ABP, patients progress to septic shock and are treated with marginally efficacious off-label vasopressors.13 This program aims to develop a new drug with a dual mechanism of action for sepsis capable to concomitantly block vasodilation and VL while eliminating resuscitation fluids. The two molecular targets selected herein to respectively block vasodilation and VL are supported by strong scientific and clinical evidence derived in part from previous team contributions to the field. The chemical feasibility to drug these two targets has already previously been established by the team, and active pharmacophores for the two targets are already available. The program will consist in 1st) demonstrating feasibility to create bi-functional molecules by covalently linking target 1 and 2 active pharmacophores (Aim 1); 2nd) demonstrating that bi-functional molecules retain activity at the two molecular targets (Aim 2); and 3rd) establishing that bi-functional molecules concomitantly block vasodilation and VL in a surrogate pharmacological model of sepsis (Aim 3). IMPACT &

项目概要脓毒症是最常见的危及生命的疾病之一，导致发达国家和地区的死亡率很高 1 仅在美国，败血症就影响了 1 至 300 万患者，导致 250,000 至 375,000 人死亡 2009 年死亡人数2，2011 年美国医院费用达 203 亿美元。3 除了复杂、冗余的医疗费用外，而且免疫反应常常存在差异，4脓毒症总是以血管舒张和血管扩张为特征。渗漏 (VL)，5-7 两个恒定、独立且互补的下游心血管致病特征直接导致器官灌注减少、组织水肿、器官功能障碍、多器官衰竭和死亡。如今，脓毒症患者最初接受抗生素治疗并给予复苏液以维持动脉血流血压（ABP）。然而，液体纯粹是症状，并不能解决症状减少的根本原因。器官灌注和功能。最令人担忧的是，它们经常导致液体超负荷，8从而进一步增加组织水肿、器官衰竭和死亡。9-12 一旦液体不再能够维持 ABP，患者就会出现病情进展败血性休克，并使用勉强有效的标签外血管升压药进行治疗。 13 该计划旨在开发一种具有双重作用机制的脓毒症新药，能够同时阻断血管舒张和 VL，同时消除复苏液。选定的两个分子靶点本文分别阻断血管舒张和 VL 得到了强有力的科学和临床证据的支持部分来自之前团队对该领域的贡献。药物这两个目标的化学可行性已经该团队之前已建立了该方法，并且已经可以获得这两个目标的活性药效团。该计划将包括 1st) 展示创建的可行性通过共价键连接形成双功能分子目标 1 和 2 活性药效基团（目标 1）； 2nd）证明双功能分子在两个分子目标（目标 2）； 3）确定双功能分子同时阻断脓毒症替代药理学模型中的血管舒张和 VL（目标 3）。影响＆