Inhibitors of Thromboinflammation for Acute Kidney Injury

Acute kidney injury (AKI) is the sudden and dangerous loss of kidney function that causes significant morbidity and mortality. A significant fraction of patients undergoing major surgery suffer from AKIs, particularly cardiac patients, with >10% probability of AKI frequently reported. Almost half of hospitalized COVID patients suffered from dangerous (and often deadly) AKIs early in the pandemic, and certain anti-cancer therapies and anti-infectives are known to cause AKIs. AKIs extend hospitalization, and even when kidney function returns to more normal levels, patients suffering from AKIs are at much greater risk of developing chronic kidney disease. Presently, there are no drugs approved by the FDA for the prevention of AKI. Function Therapeutics and its collaborating labs have discovered a new class of antithrombotic and anti-inflammatory small molecules that are biased, allosteric modulators of signaling by the thrombin receptor, protease-activated receptor 1 (PAR1). These compounds, called parmodulins, act to inhibit thromboinflammation by biasing PAR1 signaling towards an anti-inflammatory pathway. They have achieved promising results with in vitro and in vivo models of disease, including infection-promoted thrombosis, coronary ischemia-reperfusion injury, sickle cell disease, and diabetic kidney disease. We hypothesize that their effects may be ideal for the prevention and treatment of AKI in at risk patients. The objectives of this project are to 1) Optimize current lead series of parmodulins with the potential to meet a Target Product Profile suitable for hospitalized patients at risk for AKI; 2) Validate that parmodulins are efficacious in a mouse model of ischemic AKI. Parmodulins will be designed, synthesized, and tested in primary and secondary in vitro assays in an iterative fashion. Drug-like profiling, including cytotoxicity, solubility, and stability assays, will be used to identify promising parmodulins for further safety and pharmacokinetic studies. Several optimal examples will ultimately undergo efficacy studies in a mouse model of ischemic AKI, using a protocol for bilateral ischemia-reperfusion injury in the lab of Dr. James George in the O’Brien Center for Acute Kidney Injury at the University of Alabama at Birmingham. This project will help to advance a unique approach to the treatment of AKI towards clinical stages.