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

项目摘要 脓毒症是最常见的危及生命的疾病之一，导致高死亡率，无论是在发达国家， 1仅在美国，败血症就困扰着100万至300万患者，造成250，000至375，000例 2011年，美国医院成本中有203亿美元。 和经常变化的免疫反应，脓毒症的特征总是血管舒张和血管扩张。 泄漏（VL），5 -7两个恒定的、独立的和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，以及 死亡今天，败血症患者最初使用抗生素治疗，并给予复苏液以维持动脉 血压（ABP）。然而，液体纯粹是症状性的，不能解决降低的根本原因。 器官灌注和功能。最令人担忧的是，它们经常导致体液过多，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， 感染性休克，并接受勉强有效的标签外血管加压药治疗。13 该项目旨在开发一种具有双重作用机制的新药， 同时阻断血管舒张和VL，同时消除复苏液体。选择的两个分子靶点 本文中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 部分来自于之前团队对该领域的贡献。对这两个目标进行药物治疗的化学可行性已经 这两个目标的活性药效团已经可用。 该计划将包括第一）证明可行性，创造 通过共价连接的双功能分子 靶向1和2个活性药效团（目标1）; 2）证明双功能分子在 两个分子靶点（目标2）;和第3）建立双功能分子同时阻断 在败血症的替代药理学模型中的血管舒张和VL（目的3）。影响和

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 &