The functions and efficacy of mavacamten

Mavacamten (mavacamten) is a new drug mainly used to treat obstructive hypertrophic cardiomyopathy (HCM). Its mechanism of action is closely related to the function of myosin. Myosins are a family of enzymes that utilize ATP to mediate mechanical output through cyclic interactions with actin. When ATP binds to myosin heads, the activity of myosin ATPase hydrolyzes ATP into ADP and organophosphorus, and the released energy is stored in the myosin heads. As the organophosphate dissociates, myosin transitions into a state that is strongly bound to actin, forming a myosin-actin complex that produces muscle contraction.

Mavacate reduces the ATPase activity of myosin by acting as an allosteric and reversible modulator of the beta-cardiac isoform of myosin. This effect reduces cross-bridging between actin and myosin, thereby alleviating excessive contraction of the sarcomere. Specifically, Mavacate inhibits the release of phosphate, the rate-limiting step of the cycle, without affecting the rate of ADP release. In addition, it inhibits the binding of ADP-bound myosin to actin and the turnover of myosin heads triggered by ADP release.

Recent studies have found that myosin, without interacting with actin, can exist between two energy-saving states: a disordered relaxed state and a hyperrelaxed state. In the hyperrelaxed state, significant myosin head-to-head interactions prolong ATP turnover. The combination of Mavacate and myosin shifts this balance to a super-relaxed state, effectively exerting the inhibitory effect of basal and actin-activated ATP. Through this mechanism, Mavakatai can effectively improve cardiac dysfunction caused by HCM and improve patients' quality of life.

Reference materials:https://go.drugbank.com/drugs/DB14921