A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle.

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Kawas RF, Anderson RL, Ingle SRB, Song Y, Sran AS, Rodriguez HM

A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle.

J Biol Chem. 2017 Oct 6;292(40):16571-16577. doi: 10.1074/jbc.M117.776815. Epub 2017 Aug 14.

PubMed ID

28808052 [ View in PubMed

]

Abstract

Mavacamten, formerly known as MYK-461 is a recently discovered novel small-molecule modulator of cardiac myosin that targets the underlying sarcomere hypercontractility of hypertrophic cardiomyopathy, one of the most prevalent heritable cardiovascular disorders. Studies on isolated cells and muscle fibers as well as intact animals have shown that mavacamten inhibits sarcomere force production, thereby reducing cardiac contractility. Initial mechanistic studies have suggested that mavacamten primarily reduces the steady-state ATPase activity by inhibiting the rate of phosphate release of beta-cardiac myosin-S1, but the molecular mechanism of action of mavacamten has not been described. Here we used steady-state and presteady-state kinetic analyses to investigate the mechanism of action of mavacamten. Transient kinetic analyses revealed that mavacamten modulates multiple steps of the myosin chemomechanical cycle. In addition to decreasing the rate-limiting step of the cycle (phosphate release), mavacamten reduced the number of myosin-S1 heads that can interact with the actin thin filament during transition from the weakly to the strongly bound state without affecting the intrinsic rate. Mavacamten also decreased the rate of myosin binding to actin in the ADP-bound state and the ADP-release rate from myosin-S1 alone. We, therefore, conclude that mavacamten acts on multiple stages of the myosin chemomechanical cycle. Although the primary mechanism of mavacamten-mediated inhibition of cardiac myosin is the decrease of phosphate release from beta-cardiac myosin-S1, a secondary mechanism decreases the number of actin-binding heads transitioning from the weakly to the strongly bound state, which occurs before phosphate release and may provide an additional method to modulate myosin function.

DrugBank Data that Cites this Article

Drugs

Mavacamten

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Mavacamten	Myosin-7	Protein	Humans	Yes	Inhibitory allosteric modulator	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Mavacamten Ticlopidine	The serum concentration of Mavacamten can be increased when it is combined with Ticlopidine.
Mavacamten Zafirlukast	The serum concentration of Mavacamten can be increased when it is combined with Zafirlukast.
Mavacamten Efavirenz	The serum concentration of Mavacamten can be increased when it is combined with Efavirenz.
Mavacamten Sertraline	The serum concentration of Mavacamten can be increased when it is combined with Sertraline.
Mavacamten Armodafinil	The serum concentration of Mavacamten can be increased when it is combined with Armodafinil.