Omecamtiv Mecarbil Modulates the Kinetic and Motile Properties of Porcine β-Cardiac Myosin

Liu, Yingying; White, Howard D.; Belknap, Betty; Winkelmann, Donald A.; Forgács, Éva

doi:10.1021/bi5015166

Cited by 120 publications

(212 citation statements)

References 42 publications

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“…1A). This activator of cardiac myosin increases force production by the heart by increasing the transition of cardiac myosin from a weakly to strongly actin-bound state, as evidenced by a faster rate of P i release (2,10), and by slowing down the following steps of the powerstroke. In the crystal structure, omecamtiv mecarbil binds to cardiac myosin (9) in a surface pocket accessible in the PR state (Fig.…”

Section: Ck-571 Reveals the Existence Of An Allosteric Pocket Adjacenmentioning

confidence: 99%

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

Sirigu

Hartman

Planelles-Herrero

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Direct inhibition of smooth muscle myosin (SMM) is a potential means to treat hypercontractile smooth muscle diseases. The selective inhibitor CK-2018571 prevents strong binding to actin and promotes muscle relaxation in vitro and in vivo. The crystal structure of the SMM/drug complex reveals that CK-2018571 binds to a novel allosteric pocket that opens up during the "recovery stroke" transition necessary to reprime the motor. Trapped in an intermediate of this fast transition, SMM is inhibited with high selectivity compared with skeletal muscle myosin (IC 50 = 9 nM and 11,300 nM, respectively), although all of the binding site residues are identical in these motors. This structure provides a starting point from which to design highly specific myosin modulators to treat several human diseases. It further illustrates the potential of targeting transition intermediates of molecular machines to develop exquisitely selective pharmacological agents.M yosins comprise a family of ATP-dependent motor proteins capable of producing directed force via interaction with their track, the F-actin filament. Force production by these motors powers numerous cellular processes such as muscle contraction, intracellular transport, and cell migration and division (1). Several myosins have also been linked to genetic disorders where either gain or loss of motor function can lead to disease. These motor proteins represent promising targets for the development of drugs modulating force production in cells, tissues, and muscle (2-4). Here we report a selective, smallmolecule inhibitor of smooth muscle myosin (SMM) able to induce muscle relaxation. This mechanism of action has potential relevance for many diseases where smooth muscle contractility is central to the pathophysiology, such as asthma (5, 6) and chronic obstructive pulmonary disease (7).Smooth muscle contractility can be activated through different pathways. Existing airway smooth muscle relaxants, such as β-adrenergic agonists and muscarinic antagonists, ultimately inhibit the activity of SMM. However, they do so via specific upstream signaling pathways. Direct inhibition of SMM contractility has the advantage of relaxing contracted smooth muscle regardless of the molecular stimulus driving it. Moreover, application of SMM inhibitors to the airway provides a means of selectively modulating contractility of these tissues by delivering a high local concentration of drug. We thus set about identifying selective inhibitors of SMM that can effectively relax muscle in vivo, leading to the discovery of a highly selective, small-molecule inhibitor, CK-2018571 (CK-571).The detailed inhibitory mechanism of CK-571 was elucidated by a combination of in vitro characterization of the step in which the drug traps the motor and determination of the high-resolution structure of SMM cocrystallized with CK-571. The drug targets an intermediate state that occurs during the recovery stroke, the large conformational rearrangement that enables repriming of the motor. Blocking this critical transiti...

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Section: Ck-571 Reveals the Existence Of An Allosteric Pocket Adjacenmentioning

confidence: 99%

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

Sirigu

Hartman

Planelles-Herrero

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In particular, assuming that OM can induce similar effects on the pre-powerstroke state, the reduction of CLD rotational motions upon OM binding might explain the strong reduction in the powerstroke rotation rate measured with FRET [16] and the overall decrease of the actin sliding velocity [14,15]. This inhibitory effect on the lever arm motions is considered to be consistent with the overall increase in muscle contractility produced by OM binding, since it increases the fraction of time spent by myosin in the force generating state where it is strongly bound to actin [14,16].…”

Section: Discussionmentioning

confidence: 99%

“…The larger duty ratio causes an increase in the force produced by the sarcomere (ensemble force) [4], so that the overall effect of OM binding is an increased heart contractility [13]. At the same time, OM has been shown to have an inhibitory effect on the velocity of actin filaments in in vitro motility assays [14,15] and on the powerstroke rate in time resolved FRET experiments [16], while contrasting results have been found when studying its effect on the actin-activated ATP hydrolysis rate [13,15].…”

Section: Introductionmentioning

confidence: 99%

Allosteric Modulation of Cardiac Myosin Dynamics by Omecamtiv Mecarbil

Hashem

Tiberti

Fornili

2018

Biophysical Journal

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New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear. We present here a Molecular Dynamics study of the motor domain of human cardiac myosin bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution. We found that OM has a double effect on myosin dynamics, inducing a) an increased coupling of the motions of the converter and lever arm subdomains to the rest of the protein and b) a rewiring of the network of dynamic correlations, which produces preferential communication pathways between the OM binding site and distant functional regions. The location of the residues responsible for these effects suggests possible strategies for the future development of improved drugs and the targeting of specific cardiomyopathy-related mutations. Author summaryCardiac myosin is a motor protein responsible for the contraction of the heart muscle. New strategies for the cure of heart diseases are currently being developed by using myosin modulators, which are small molecules that can interact with myosin and modify its activity. The advantage of this approach over traditional drugs is that by directly targeting cardiac myosin it is possible to have drugs with reduced side effects. Moreover, the availability of a spectrum of molecules to finely tune myosin to a desired level of activity opens the possibility to develop more precise and personalised drug therapies. In this work, we study a recently discovered activator of cardiac myosin, omecamtiv mecarbil, in order to understand its mechanism of action. In particular, we use Molecular Dynamics simulations to unravel the effects of the drug on myosin motions, which are closely related to its PLOS Computational Biology | https://doi

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“…Tehát egyáltalán nem zárható ki, hogy az OM a P i -disszociá-ció ütemének fokozásán kívül mást is tesz az aktin-miozin ciklussal (46)(47)(48). In vitro motilitási vizsgálatokban is megerősítették, hogy OM hatására csökken az aktin fi lamentumok miozin-függő elmozdulásának sebessé-ge (38,46). Az in vitro kinetikai és motilitási adatok jól korreláltak az in vivo preklinikai és klinikai vizsgálatok eredményeivel is.…”

Section: Klinikai Vizsgálati Eredmények Omecamtiv Mecarbillalunclassified

“…Ösz-szességében, OM hatására hosszabb ideig tartó aktív kontrakció jön létre, a relaxáció lassulásával (27,49). Végeredményben tehát az OM-et a szó szigorú értel-mében nem tekinthetjük egyszerűen miozin-aktivátor-nak, sokkal inkább az aktin-miozin rendszer alloszterikus modulátorának, amely a myocardium konktraktilis funkcióját a Ca 2+ -érzékenység fokozásán keresztül tá-mogatja (46).…”

Section: Klinikai Vizsgálati Eredmények Omecamtiv Mecarbillalunclassified

A szív pozitív inotróp támogatása a miozin-aktivátor hatású omecamtiv mecarbil segítségével

Nagy¹,

Gődény²,

Nánási³

et al. 2017

Cardiologia Hungarica

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Jelenleg a kereskedelmi forgalomban még nem érhetőek el a szív mechanikai funkciójának támogatására azok az újnak tekintett gyógyszerek, amelyekre, mint kardiális miozin-aktivátorok hivatkoznak. Az omecamtiv mecarbil, mint a csoport egyetlen ismert képviselője előzetes preklinikai vizsgálatokban hatékonynak tűnt. Továbbá bíztató eredmé-nyek láttak napvilágot a már lezárt I. és II. fázis klinikai vizsgálatokban is. A vegyület pontos hatásmechanizmusával és biztonságosságával kapcsolatban azonban még nem rendelkezünk kiterjedt ismeretekkel. Jelen áttekintés célja az, hogy a rendelkezésre álló laboratóriumi és klinikai adatok tükrében értékelje az omecamtiv mecarbil várható klinikai használhatóságát. Inotropic therapy with the myosin activator omecamtiv mecarbilThe novel cardiotonic drugs, called cardiac myosin activators have not been commercialized for clinical administrations yet. Omecamtiv mecarbil, the only known representative of the above class of drugs, appeared to be effective in preclinical investigations. Moreover, promising results have been also reported for phase I and phase II clinical trials as well. Nevertheless, our understanding on the exact mechanism of action and safety of omecamtiv mecarbil is still limited. The aim of the present overview is to summarize the currently available preclinical and clinical data on omecamtiv mecarbil, and thereby to estimate its potential clinical benefi t. BevezetésMelyek az ideális pozitív inotróp vegyület-tel szemben támasztott elvárások? Napjainkra már többszörösen igazolt tény, hogy a szív pumpafunkcióját támogató konvencionális pozitív inotróp hatású gyógyszerek alkalmazása -a kedvező hemodinamikai hatások dacára -nem problémamentes, hiszen alkalmazásuk fokozott mortalitással járhat (1-3).Mivel minden szempontból meggyőző pozitív inotróp hatású szer továbbra sem áll a rendelkezésünkre, az inotrópia a farmakológiai kutatások számára ma is cél-területként szerepel. A kívánatos az lenne, ha olyan kardiotonikus szereket sikerülne kifejleszteni, amelyek úgy javítanák a myocardium teljesítményét, hogy ezzel párhuzamosan nem fokozódna a szív oxigénfogyasztá-sa. Az ideális pozitív inotróp szerekkel szemben továb-myosin activators, omecamtiv mecarbil, positive inotropy, heart failure, Ca 2+ sensitiser positive inotrope agents Kulcsszavak:Keywords:miozin-aktivátorok, omecamtiv-mecarbil, pozitív inotrópia, szívelégtelenség, Ca 2+ -érzékenyítő pozitív inotróp vegyületek

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Omecamtiv Mecarbil Modulates the Kinetic and Motile Properties of Porcine β-Cardiac Myosin

Cited by 120 publications

References 42 publications

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

Allosteric Modulation of Cardiac Myosin Dynamics by Omecamtiv Mecarbil

A szív pozitív inotróp támogatása a miozin-aktivátor hatású omecamtiv mecarbil segítségével

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