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

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

doi:10.1172/jci148557

Cited by 43 publications

(45 citation statements)

References 68 publications

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“…Mavacamten is a small molecule that belongs to the myosin modulators, a novel class of pharmaceutical agents that are being developed to treat patients with a range of cardio-myopathies. Myosin modulators are often classified as either “myosin activators” (omecamtiv, danicamtiv) or “myosin inhibitors” (mavacamten, aficamten) [ 80 ]. The therapeutic goal of these drugs is to target cardiac myosins directly to modulate contractility and cardiac power output, in order to alleviate symptoms that lead to heart failure and arrhythmias without changes in calcium signaling [ 81 ].…”

Section: Treatment Modalities Targeting Diseases Of the Ivsmentioning

confidence: 99%

The Interventricular Septum: Structure, Function, Dysfunction, and Diseases

Triposkiadis

Xanthopoulos

Boudoulas

et al. 2022

JCM

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Vertebrates developed pulmonary circulation and septated the heart into venous and arterial compartments, as the adaptation from aquatic to terrestrial life requires more oxygen and energy. The interventricular septum (IVS) accommodates the ventricular portion of the conduction system and contributes to the mechanical function of both ventricles. Conditions or diseases that affect IVS structure and function (e.g., hypertrophy, defects, other) may lead to ventricular pump failure and/or ventricular arrhythmias with grave consequences. IVS structure and function can be evaluated today using current imaging techniques. Effective therapies can be provided in most cases, although definitions of underlying etiologies may not always be easy, particularly in the elderly due to overlap between genetic and acquired causes of IVS hypertrophy, the most common being IVS abnormality. In this review, state-of-the-art information regarding IVS morphology, physiology, physiopathology, and disease is presented.

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Section: Treatment Modalities Targeting Diseases Of the Ivsmentioning

confidence: 99%

The Interventricular Septum: Structure, Function, Dysfunction, and Diseases

Triposkiadis

Xanthopoulos

Boudoulas

et al. 2022

JCM

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“…The development of small molecules able to specifically activate or inhibit myosin force production has been successful in several other myosin classes, including the first-in-class activator Omecamtiv mecarbil (OM) and the first-in-class inhibitor Mavacamten, targeting β-cardiac myosin against heart failure and inherited cardiac diseases 13,14,15 ; MPH-220, an inhibitor of skeletal muscle myosin (SkMyo2) against muscular spasticity 16 ; and CK-571, a smooth muscle myosin 2 inhibitor (SmMyo2) against asthma 17 ; reviewed by 18,19,20 . The fact that some of these compounds such as OM and Mavacamten have completed phase 3 clinical trials 21,22 gives significant confidence to the development of myosins as realistic and druggable targets.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design

Moussaoui

Robblee

Auguin

et al. 2022

Preprint

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Malaria is responsible for more than a half million deaths per year. The Plasmodium parasites responsible continue to develop resistance to all known agents, despite treatment with different antimalarial combinations. The atypical Myosin A motor (PfMyoA) is part of a core macromolecular complex called the glideosome, essential for Plasmodium parasite mobility and therefore an attractive drug target. Here, we characterize the interaction of a small molecule (KNX-002) with PfMyoA. KNX-002 inhibits PfMyoA ATPase activity in vitro and blocks asexual blood stage growth of merozoites, one of three motile Plasmodium life-cycle stages. Combining biochemical assays, X-ray crystallography and molecular dynamics, we demonstrate that KNX-002 targets a novel pocket in PfMyoA, sequestering it in a post-rigor state detached from actin. KNX-002 binding affects Mg2+ coordination near ATP, preventing ATP hydrolysis and thus inhibiting motor activity. This first-in-class small-molecule inhibitor of PfMyoA paves the way for developing a new generation of antimalarial treatments.

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“…Sarcomeric contractile activators directly increase the sensitivity of thin lament to Ca 2+ or increase myosin ATPase activity. Levosimendan could increase the contractility of myocardium by improving the a nity between calcium and troponin C [25][26] and enhancing the sensitivity of thin lament to Ca 2+ , while Danicamtiv and Omecamtiv mecarbil 27 stimulate myocardial contractility by increasing myosin ATPase activity. In this network meta-analysis, the population we studied was patients with heart failure with reduced ejection fraction (LVEF < 40%).…”

Section: Discussionmentioning

confidence: 99%

The efficacy and safety of sarcomeric contractile activators in patients with reduced ejection fraction in heart failure: a network meta-analysis

Zhao

et al. 2022

Preprint

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Background: Sarcomeric contractile activators are small molecules that target myocardium to increase contractility. So far, great progress has been achieved regarding their preventive actions against idiopathic heart failure. Specifically, Levosimendan, Omecamtiv mecarbil and Danicamtiv are all sarcomeric contractile activators, while, to date, direct comparative studies of these drugs in the treatment of heart failure patients with reduced ejection fraction (HFrEF) are lacking. Methods: Network meta-analysis was conducted to compare the efficacy and safety of these drugs in HFrEF patients. The primary endpoint was heart rate, and the secondary endpoints were all-cause death, dizziness, hypotension as well as cardiac failure events. Results: A total of 22 randomized controlled trials involving 11410 participants were included. Omecamtiv mecarbil was superior to placebo (1.64(1.12, 2.17)) and Levosimendan (2.96(0.39, 5.55)) in controlling heart rate. The incidence of all-cause death caused by Levosimendan was lower than placebo (0.05(-0.47, 0.58)) and Omecamtiv mecarbil (0.05(-0.48, 0.59)). The incidence of cardiac failure events caused by Levosimendan was lower than placebo (-0.19(-0.46, 0.09)) and Omecamtiv mecarbil (-0.11(-0.40, 0.18)). Conclusions: In HFrEF patients, Omecamtiv mecarbil was superior to placebo and Levosimendan in controlling heart rate. Levosimendan induced all-cause death and cardiac failure events better than placebo and Omecamtiv mecarbil in HFrEF patients.

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

Cited by 43 publications

References 68 publications

The Interventricular Septum: Structure, Function, Dysfunction, and Diseases

The Interventricular Septum: Structure, Function, Dysfunction, and Diseases

Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design

The efficacy and safety of sarcomeric contractile activators in patients with reduced ejection fraction in heart failure: a network meta-analysis

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