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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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 3

A hypothetical model of the relationships between SRX, DRX, and actin-activated states of myosin and effects of drugs.

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A hypothetical model of the relationships between SRX, DRX, and actin-ac...
The three states of myosin — SRX, DRX, and actin-activated — are diagrammed. The motor domains in a myosin molecule are proposed to interact with each other and the thick filament to form the IHM in the SRX state. While in the SRX state, the myosins are not available to interact with actin, and they are not involved in muscle contractility. Mavacamten is proposed to stabilize the SRX state. Myosins in the DRX state do not interact with the thick filament and are available to bind to actin in response to thin filament activation. Myosins in the actin-activated state bind to actin and undergo their mechanochemical cycle as outlined in Figure 1.