Professor L. Michel Espinoza-Fonseca
Center for Arrhythmia Research
U. of Michigan
Ann Arbor, MI

Monday, September 30, 2019
3:00 pm (CT)
3269 Beckman Institute

Abstract

Sarcoplasmic reticulum calcium ATPase (SERCA) is a transmembrane pump critical for calcium transport from the cytosol to the lumen of the sarcoplasmic reticulum (SR). Deregulation and deactivation of this essential component in the calcium transport machinery is a hallmark of heart failure, so development of SERCA activating drugs has emerged as a promising approach for the pharmacological treatment of this condition. My group focuses on a comprehensive computer-to- bedside approach for the design of novel small-molecule SERCA activators. The best molecules are then synthetized and experimentally tested in situ for SERCA activity and in vitro for efficacy using patient-derived iPSC cardiomyocytes. We found that the molecules designed in the computer activate the calcium pump in the low µM range and also stimulate intracellular calcium transport in human iPSC cardiomyocytes at nM concentrations. Our most exciting discovery is that the most promising SERCA activators reverses calcium mishandling and protects the cardiomyocyte against arrhythmia in a clinically relevant model of heart disease, with no apparent long-term cardiotoxicity. These results demonstrate that our computer-to-bedside strategy for drug design accelerates the discovery of promising drug-like molecules for the pharmacological treatment of heart failure.