Development of Novel Small-Molecule Therapies for the Treatment of Heart Failure

Abstract

Sarco(endo)plasmic 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 the development of SERCA activating drugs has emerged as a promising approach for the pharmacological treatment of this condition. We have performed extensive structural analyses to understand the key structural features associated with SERCA activation, and to use this information for the discovery and development of small-molecule SERCA activators. We combined this structural analysis with a series of cheminformatics and de novo structure-based drug design techniques to design a new series of novel SERCA activators in silico. The best small-molecule candidates were 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 comprehensive structure-based strategy for drug design accelerates the discovery of novel drug-like molecules for the pharmacological treatment of heart failure.