Novel Integrin Inhibitors for Kidney Fibrosis Chronic Kidney Disease (CKD) currently affects over 20 million people in the US and is a significant healthcare burden world-wide with treatment of U.S. individuals with end-stage renal disease (ESRD) costing Medicare over $32 billion in 2010. Despite treatment of CKD with Reno protective agents, there is currently no therapy that slows or halts disease progression and individuals frequently progress to ESRD. Irrespective of the cause of CKD, fibrosis is a key underlying feature and plays a major role in progression to ESRD. Fibrosis is characterized by the abnormal deposition of extracellular matrix components including collagen within the glomeruli and along the tubules of the kidneys. In the last decade significant improvements in technologies and the availability of clinical data have accelerated our understanding of the underlying kidney changes associated with disease progression, contributing to the identification and evaluation of potential new therapeutics. The regulation of matrix components depends on many factors; including cytokines, oxidative stress, and cell- matrix interactions via integrin. Integrin are heterodimeric transmembrane receptors consisting of an ? and ? subunit non-covalently bound. Upon ligand binding, these receptors activate intracellular signaling able to control various functions including matrix synthesis/degradation. The integrin we focus on is a collagen receptor and contributes to kidney fibrosis by positively regulating collagen production. In support of this finding, genetic and pharmacological inhibition of this receptor in mice ameliorates kidney fibrosis following injury. These data suggest that inhibition of this receptor might be beneficial in the setting of fibrotic diseases. The goal of this proposal is to design novel, selective small-molecule allosteric inhibitors of this integrin. The grant seeks to ascertai inhibitors of this integrin that possess significant improvement in pharmaceutical properties over currently available molecules, in order to develop an orally active inhibitor suitable for further pre-clinical and clinical validation for fibrotic diseases. The activity and selectivity of these nvel inhibitors will be initially determined in vitro by investigating their ability to i) block cell adesion to collagen in a manner selective to the integrin of interest, and ii) prevent integrin-mediated collagen synthesis in kidney cells. Two of the most promising compounds will be tested in mice to determine their ability to reduce adriamycin-mediated albuminuria and glomerulosclerosis. Positive results will initiate funding proposals for proof-of-concept studies in more advanced models of fibrosis, particularly diabetic nephropathy, and optimization of the molecules for clinical testing.
