Myosin modulators: emerging approaches for the treatment of cardiomyopathies and heart failure
Sharlene M. Day, … , Jil C. Tardiff, E. Michael Ostap
Sharlene M. Day, … , Jil C. Tardiff, E. Michael Ostap
Published March 1, 2022
Citation Information: J Clin Invest. 2022;132(5):e148557. https://doi.org/10.1172/JCI148557.
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Review Series

Myosin modulators: emerging approaches for the treatment of cardiomyopathies and heart failure

Abstract

Myosin modulators are a novel class of pharmaceutical agents that are being developed to treat patients with a range of cardiomyopathies. The therapeutic goal of these drugs is to target cardiac myosins directly to modulate contractility and cardiac power output to alleviate symptoms that lead to heart failure and arrhythmias, without altering calcium signaling. In this Review, we discuss two classes of drugs that have been developed to either activate (omecamtiv mecarbil) or inhibit (mavacamten) cardiac contractility by binding to β-cardiac myosin (MYH7). We discuss progress in understanding the mechanisms by which the drugs alter myosin mechanochemistry, and we provide an appraisal of the results from clinical trials of these drugs, with consideration for the importance of disease heterogeneity and genetic etiology for predicting treatment benefit.

Authors

Sharlene M. Day, Jil C. Tardiff, E. Michael Ostap

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Figure 1

Myosin mechanochemical cycle.

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Myosin mechanochemical cycle. The relationship of the biochemical and co...
The relationship of the biochemical and conformational states of cardiac myosin is shown as the motor progresses through the ATPase cycle. For clarity, myosin molecules are illustrated with single motor domains. The force-generating working stroke occurs with phosphate release (step v). OM was originally developed to increase the rate of this transition, but subsequent studies have shown that it also affects the working stroke and subsequent kinetic steps. Danicamtiv likely works by the same mechanism, but biochemical analyses have not been performed to confirm this. The SRX-to-DRX transition is shown as an off-ATPase-pathway transition. Mavacamten is thought to stabilize the SRX state (see text and Figure 3), and presumably aficamten acts similarly in this regard. Adapted with permission from Biophysical Journal (12).