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.

Figure 1. Myosin mechanochemical cycle.

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).

Figure 2. SEPTA model for the mechanism of action of OM.

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 P_i 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.

Figure 3. A hypothetical model of the relationships between SRX, DRX, and actin-activated states of myosin and effects of drugs.

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.