Small molecule studies: the fourth wave of muscle research

Marston, Steven B.

doi:10.1007/s10974-019-09526-w

Cited by 9 publications

(14 citation statements)

References 83 publications

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“…In the past decade, interest in developing small molecules that can act directly on the contractile apparatus have emerged. This phase of research was suggested as the “fourth wave” of muscle research [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…It was proposed that a small-molecule fast-skeletal–troponin activator, would increase muscle strength in myopathy due to mutations in contractile proteins but could also be useful by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease [ 64 ]. This is possible because, unlike cardiac muscle, skeletal muscle has the advantage of being regenerative thus muscle activation can promote muscle growth [ 65 ]. A screen for Ca 2+ sensitising agents that target fast skeletal muscle troponin by Cytokinetics yielded the following compounds: Tirasemtiv (or CK-2017357), Reldesemtiv (or CK-2127107) and CK-2066260.…”

Section: Contractile Activators As Treatments For Heart Failure Anmentioning

confidence: 99%

“…Four small molecules can regulate the transition, as shown. Figure was created by using Biorender.com as a modified version from References [ 65 , 83 ].…”

Section: Figurementioning

confidence: 99%

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Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases

Alsulami

Marston

2020

IJMS

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Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most prevalent forms of the chronic and progressive pathological condition known as cardiomyopathy. These diseases have different aetiologies; however, they share the feature of haemodynamic abnormalities, which is mainly due to dysfunction in the contractile proteins that make up the contractile unit known as the sarcomere. To date, pharmacological treatment options are not disease-specific and rather focus on managing the symptoms, without addressing the disease mechanism. Earliest attempts at improving cardiac contractility by modulating the sarcomere indirectly (inotropes) resulted in unwanted effects. In contrast, targeting the sarcomere directly, aided by high-throughput screening systems, could identify small molecules with a superior therapeutic value in cardiac muscle disorders. Herein, an extensive literature review of 21 small molecules directed to five different targets was conducted. A simple scoring system was created to assess the suitability of small molecules for therapy by evaluating them in eight different criteria. Most of the compounds failed due to lack of target specificity or poor physicochemical properties. Six compounds stood out, showing a potential therapeutic value in HCM, DCM or heart failure (HF). Omecamtiv Mecarbil and Danicamtiv (myosin activators), Mavacamten, CK-274 and MYK-581 (myosin inhibitors) and AMG 594 (Ca2+-sensitiser) are all small molecules that allosterically modulate troponin or myosin. Omecamtiv Mecarbil showed limited efficacy in phase III GALACTIC-HF trial, while, results from phase III EXPLORER-HCM trial were recently published, indicating that Mavacamten reduced left ventricular outflow tract (LVOT) obstruction and diastolic dysfunction and improved the health status of patients with HCM. A novel category of small molecules known as “recouplers” was reported to target a phenomenon termed uncoupling commonly found in familial cardiomyopathies but has not progressed beyond preclinical work. In conclusion, the contractile apparatus is a promising target for new drug development.

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Section: Discussionmentioning

confidence: 99%

Section: Contractile Activators As Treatments For Heart Failure Anmentioning

confidence: 99%

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Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases

Alsulami

Marston

2020

IJMS

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“…Each tropomyosin molecule interacts with seven actin monomers, and also binds one troponin complex [39]. The troponin complex has three components, troponin-C (Tn-C), which reversibly binds calcium ions in the physiological range, troponin-I (Tn-I), which is inhibitory, and troponin T, which interacts with tropomyosin [3,39,42,43]. For more details of thin filaments see reference [39].…”

Section: Striated Muscle Sarcomeres and The Contractile Mechanismmentioning

confidence: 99%

Special Issue: The Actin-Myosin Interaction in Muscle: Background and Overview

Squire

2019

IJMS

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Muscular contraction is a fundamental phenomenon in all animals; without it life as we know it would be impossible. The basic mechanism in muscle, including heart muscle, involves the interaction of the protein filaments myosin and actin. Motility in all cells is also partly based on similar interactions of actin filaments with non-muscle myosins. Early studies of muscle contraction have informed later studies of these cellular actin-myosin systems. In muscles, projections on the myosin filaments, the so-called myosin heads or cross-bridges, interact with the nearby actin filaments and, in a mechanism powered by ATP-hydrolysis, they move the actin filaments past them in a kind of cyclic rowing action to produce the macroscopic muscular movements of which we are all aware. In this special issue the papers and reviews address different aspects of the actin-myosin interaction in muscle as studied by a plethora of complementary techniques. The present overview provides a brief and elementary introduction to muscle structure and function and the techniques used to study it. It goes on to give more detailed descriptions of what is known about muscle components and the cross-bridge cycle using structural biology techniques, particularly protein crystallography, electron microscopy and X-ray diffraction. It then has a quick look at muscle mechanics and it summarises what can be learnt about how muscle works based on the other studies covered in the different papers in the special issue. A picture emerges of the main molecular steps involved in the force-producing process; steps that are also likely to be seen in non-muscle myosin interactions with cellular actin filaments. Finally, the remarkable advances made in studying the effects of mutations in the contractile assembly in causing specific muscle diseases, particularly those in heart muscle, are outlined and discussed.

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“…Skeletal muscle actin mutations account for about 20% of congenital myopathies and occur as nemaline, intranuclear rod and/or actin myopathy, and congenital fiber-type disproportion ( 9 , 10 ). Even more importantly, cardiac actin mutations that appear in the myosin or tropomyosin-binding regions cause either hypertrophic (HCM) or dilated (DCM) cardiomyopathies ( 11 ), increasing the motivation to discover small molecules that target actin for therapeutic treatment of actin-related diseases ( 12 , 13 ).…”

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Mechanistic analysis of actin-binding compounds that affect the kinetics of cardiac myosin–actin interaction

Roopnarine

Thomas

2021

Journal of Biological Chemistry

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Actin–myosin mediated contractile forces are crucial for many cellular functions, including cell motility, cytokinesis, and muscle contraction. We determined the effects of ten actin-binding compounds on the interaction of cardiac myosin subfragment 1 (S1) with pyrene-labeled F-actin (PFA). These compounds, previously identified from a small-molecule high-throughput screen (HTS), perturb the structural dynamics of actin and the steady-state actin-activated myosin ATPase activity. However, the mechanisms underpinning these perturbations remain unclear. Here we further characterize them by measuring their effects on PFA fluorescence, which is decreased specifically by the strong binding of myosin to actin. We measured these effects under equilibrium and steady-state conditions, and under transient conditions, in stopped-flow experiments following addition of ATP to S1-bound PFA. We observed that these compounds affect early steps of the myosin ATPase cycle to different extents. They increased the association equilibrium constant K 1 for the formation of the strongly bound collision complex, indicating increased ATP affinity for actin-bound myosin, and decreased the rate constant k + 2 for subsequent isomerization to the weakly bound ternary complex, thus slowing the strong-to-weak transition that actin–myosin interaction undergoes early in the ATPase cycle. The compounds' effects on actin structure allosterically inhibit the kinetics of the actin–myosin interaction in ways that may be desirable for treatment of hypercontractile forms of cardiomyopathy. This work helps to elucidate the mechanisms of action for these compounds, several of which are currently used therapeutically, and sets the stage for future HTS campaigns that aim to discover new drugs for treatment of heart failure.

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Small molecule studies: the fourth wave of muscle research

Cited by 9 publications

References 83 publications

Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases

Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases

Special Issue: The Actin-Myosin Interaction in Muscle: Background and Overview

Mechanistic analysis of actin-binding compounds that affect the kinetics of cardiac myosin–actin interaction

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