Molecular Insights into Drug Therapies for Systolic Heart Failure

Advances in understanding the structural basis for cardiac myosin motor function have been reported by CABM members Ann Stock, professor of biochemistry and molecular biology at RWJMS, and Matthew Miller, assistant research professor of chemistry and chemical biology at Rutgers-New Brunswick, as part of a multidisciplinary collaborative project involving Eva Forgacs, associate professor of physiological sciences at Eastern Virginia Medical School and research team leader Donald Winklemann, professor of pathology and laboratory medicine at RWJMS. The study, reported in Nature Communications, provides the first atomic resolution structure of a human myosin motor domain, and of a cardiac myosin. The structure was determined as a complex with omecamtiv mecarbil (OM), a drug in clinical trials for treatment of systolic heart failure.

Heart failure is a common human disease with a significant lifetime risk that increases with age. In its most common manifestation, heart failure is marked by a decrease in cardiac contractility culminating in systolic heart failure. Recently, a novel approach to treatment of systolic heart failure has been developed based on pharmacologic agents called ‘cardiac myosin activators’ that bind directly to myosin and target the kinetic mechanism driving contraction. Winkelmann and colleagues performed a detailed kinetic analysis of β-cardiac myosin that determined how OM, a drug developed by Cytokinetics, Inc., modulates the motor activity of myosin. The structure of the human β-cardiac motor domain with bound drug reveals details of the mechanism of drug action that controls the kinetic and mechanical tuning of cardiac myosin, specifically increasing power output at the expense of speed of contraction. This structural analysis characterizes a highly significant binding cleft for drugs that may be exploited for development of pharmacologic agents with expanded utility.