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

• 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
• 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

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 &

项目总结 脓毒症是最常见的威胁生命的疾病之一，导致两种疾病的高死亡率。 1仅在美国，脓毒症患者就达100万至300万，造成25万至375,000人死亡 2009年死亡2，占2011.3年度美国医院费用的203亿美元，此外还有复杂、多余的 而且常常有不同的免疫反应，败血症总是以血管扩张和血管为特征 漏气(VL)，5-7两种恒定、独立、互补的心血管下游致病特征 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，以及 死亡。今天，脓毒症患者最初使用抗生素治疗，并给予复苏液体以维持动脉。 血压(ABP)。然而，液体纯粹是有症状的，并不能解决减少的根本原因 器官灌注量和功能。最令人担忧的是，它们往往会导致液体超载，8从而进一步增加 组织水肿、器官衰竭和死亡率。9-12一旦液体不能再维持ABP，患者就会进展 对于感染性休克，使用略微有效的标签外血管增压剂治疗。 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 同时阻断血管扩张和室上性心动过速，同时清除复苏液体。选定的两个分子靶点 在此，分别阻断血管扩张和VL得到了强有力的科学和临床证据的支持 这在一定程度上是因为之前球队对这一领域的贡献。对这两个靶点下药的化学可行性已经 这两个靶点的活性药效团已经可用。 该计划将包括：1)论证创建 共价键连接的双功能分子 目标1和2活性药效团(目标1)；2)显示双功能分子在 两个分子靶点(目标2)；和3)建立双功能分子同时阻断 脓毒症替代药理学模型中的血管扩张和室性早搏(目标3)。影响和