Mavacamten Inhibits the Effect of the N-Terminal Fragment of Cardiac Myosin-Binding Protein C with the L352P Mutation on the Actin–Myosin Interaction at Low Calcium Concentrations

Hypertrophic cardiomyopathy (HCM)-associated mutations in sarcomeric proteins lead to the disruption of the actin-myosin interaction and its calcium regulation and cause myocardial hypercontractility. About half of such mutations are found in the <i>MYBPC3</i> gene encoding cardiac myosin-binding protein C (cMyBP-C). A new approach to normalize cardiac contractile function in HCM is the use of β-cardiac myosin function inhibitors, one of which is mavacamten. We studied the effect of mavacamten on the calcium regulation of the actin-myosin interaction using isolated cardiac contractile proteins in the <i>in vitro</i> motility assay. The L352P mutation did not affect the maximum sliding velocity of regulated thin filaments on myosin in the <i>in vitro</i> motility assay and the calcium sensitivity of the velocity but led to the underinhibition of the actin-myosin interaction at low calcium concentrations. Mavacamten decreased the maximum sliding velocity of thin filaments in the presence of the WT and L352P C0-C2 fragments, and abolished their movement in the presence of the L352P C0-C2 fragment at low calcium concentrations. Slowing down the kinetics of cross-bridges and inhibition of actin-myosin interaction at low calcium concentrations by mavacamten may reduce the hypercontractility in HCM and the degree of myocardial hypertrophy.