作者
Fady I. Malik,James J. Hartman,Kathleen A. Elias,Bradley P. Morgan,Hector P. Rodriguez,Katjuša Brejc,Robert L. Anderson,Sandra H. Sueoka,Kenneth Lee,Jeffrey T. Finer,Roman Sakowicz,Ramesh Baliga,David R. Cox,Marc Garard,Guillermo Godinez,Raja Kawas,Erica Kraynack,David Lenzi,Pu Ping Lu,Alexander Muci,Congrong Niu,Xiangping Qian,Daniel W. Pierce,Maria Pokrovskii,Ion Suehiro,Sheila Sylvester,Todd Tochimoto,Corey Valdez,Wenyue Wang,Tatsuo Katori,David A. Kass,You Tang Shen,Stephen F. Vatner,David J. Morgans
摘要
Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.