Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil

Omecamtiv mecarbil (OM), a putative heart failure therapeutic, increases cardiac contractility. We hypothesize that it does this by changing the structural kinetics of the myosin powerstroke. We tested this directly by performing transient time-resolved FRET on a ventricular cardiac myosin biosensor. Our results demonstrate that OM stabilizes myosin’s prepowerstroke structural state, supporting previous measurements showing that the drug shifts the equilibrium constant for myosin-catalyzed ATP hydrolysis toward the posthydrolysis biochemical state. OM slowed the actin-induced powerstroke, despite a twofold increase in the rate constant for actin-activated phosphate release, the biochemical step in myosin’s ATPase cycle associated with force generation and the conversion of chemical energy into mechanical work. We conclude that OM alters the energetics of cardiac myosin’s mechanical cycle, causing the powerstroke to occur after myosin weakly binds to actin and releases phosphate. We discuss the physiological implications for these changes.

Download Full-text

Omecamtiv mecarbil: a new cardiac myosin activator for the treatment of heart failure

Expert Opinion on Investigational Drugs ◽

10.1517/13543784.2016.1123248 ◽

2015 ◽

Vol 25 (1) ◽

pp. 117-127 ◽

Cited By ~ 18

Author(s):

Licette CY Liu ◽

Bernard Dorhout ◽

Peter van der Meer ◽

John R Teerlink ◽

Adriaan A Voors

Keyword(s):

Heart Failure ◽

Cardiac Myosin ◽

Omecamtiv Mecarbil

Download Full-text

Myosin with hypertrophic cardiac mutation R712L has a decreased working stroke which is rescued by omecamtiv mecarbil

eLife ◽

10.7554/elife.63691 ◽

2021 ◽

Vol 10 ◽

Author(s):

Aaron Snoberger ◽

Bipasha Barua ◽

Jennifer L Atherton ◽

Henry Shuman ◽

Eva Forgacs ◽

...

Keyword(s):

Heart Failure ◽

Atpase Activity ◽

Binding Site ◽

Single Molecule ◽

Cardiac Failure ◽

Flow Chamber ◽

Severe Form ◽

Gliding Motility ◽

Cardiac Myosin ◽

Omecamtiv Mecarbil

Hypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout β-cardiac myosin, including in the motor domain, are associated with HCM. A β-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near-normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal β-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

Download Full-text

Human hypertrophic cardiomyopathy mutation R712L suppresses the working stroke of cardiac myosin and can be rescued by omecamtiv mecarbil

10.1101/2020.10.02.323782 ◽

2020 ◽

Cited By ~ 1

Author(s):

Aaron Snoberger ◽

Bipasha Barua ◽

Jennifer L. Atherton ◽

Henry Shuman ◽

Eva Forgacs ◽

...

Keyword(s):

Heart Failure ◽

Hypertrophic Cardiomyopathy ◽

Atpase Activity ◽

Single Molecule ◽

Cardiac Failure ◽

Flow Chamber ◽

Severe Form ◽

Gliding Motility ◽

Cardiac Myosin ◽

Omecamtiv Mecarbil

AbstractHypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout β-cardiac myosin, including in the motor domain, are associated with HCM. A β-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal β-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

Download Full-text