Bi Functional Peptides to Block Vasodilation and Vascular Leakage in Sepsis

PROJECT SUMMARY Sepsis is one of the most common life threatening illness leading to high mortality rates in both developed and developing countries In the US alone sepsis afflicted to million patients caused to deaths in and accounted for $ billion of US hospital costs in Besides the complex redundant and often variable immunological responses sepsis is always characterized by vasodilation and vascular leakage VL 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 thereby further increasing tissue edema organ failure and mortality Once fluids are no longer able to sustain ABP patients progress to septic shock and are treated with marginally efficacious off label vasopressors 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 st demonstrating feasibility to create bi functional molecules by covalently linking target and active pharmacophores Aim nd demonstrating that bi functional molecules retain activity at the two molecular targets Aim and rd establishing that bi functional molecules concomitantly block vasodilation and VL in a surrogate pharmacological model of sepsis Aim IMPACT andamp PROJECT NARRATIVE The proposed program aims to develop a new drug with a dual mechanism of action for resuscitation in sepsis that is capable to concomitantly block vasodilation and vascular leakage thus eliminating the need for resuscitation fluids