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 2

SEPTA model for the mechanism of action of OM.

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SEPTA model for the mechanism of action of OM. The regulated thin filame...
The regulated thin filament is diagrammed, with the myosin binding sites blocked by tropomyosin (blue line) in the absence of calcium. Calcium shifts the position of tropomyosin from a “blocked” state to a “closed” state. While in the closed state, the tropomyosin occasionally shifts to reveal the “open” state of the thin filament. Rapid actin binding and Pi release by OM-bound myosin stabilize the open state of the thin filament. Although OM-bound myosin has an inhibited working stroke, its prolonged time of actin attachment keeps the thin filament in the open state, allowing non-OM-bound myosins to attach and undergo uninhibited working strokes. For clarity, myosin molecules are illustrated with single motor domains.