First-in-class drug candidate (MPH-220) efficiently improves spastic gait disorders by selective inhibition of fast skeletal muscle myosin-2

Gyimesi, Máté; Horváth, Ádám I.; Túrós, Demeter; Kumar, Sunita; Pénzes, Máté; Canon, Louise; Kikuti, Carlos; Ruppel, Kathleen M.; Trivedi, Darshan V.; Spudich, James A.; Rauscher, Anna Á.; Kovács, Mihály; Komoly, Sámuel; Houdusse, Anne; Málnási‐Csizmadia, András

doi:10.1016/j.bpj.2021.11.1291

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“…Cardiomyopathies can result from distinct mutations and the description of the OM/Mava pocket opens the door to exploring how to modify the potency of these derivatives for customizable effects on force production depending on the pathological phenotype to be corrected. Such a rational approach will also be of interest for other myosins since modulators are being studied to target other myosin-associated pathologies such as spasticity by targeting SkMyo2 44 ; malaria by targeting myosin A 35,36,45 , or asthma by targeting SmMyo2 46 .…”

Section: Discussionmentioning

confidence: 99%

Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction

Auguin,

Robert-Paganin,

Réty

et al. 2023

Preprint

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SummaryInherited cardiomyopathies are amongst the most common cardiac diseases worldwide, leading in the late-stage to heart failure and death. The most promising treatments against these diseases are small-molecules directly modulating the force produced by β-cardiac myosin, the molecular motor driving heart contraction. Two of these molecules that produce antagonistic effects on cardiac contractility have completed clinical phase 3 trials: the activatorOmecamtiv mecarbiland the inhibitorMavacamten. In this work, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All atoms molecular dynamics simulations reveal how these molecules can have antagonistic impact on the allostery of the motor by comparing β-cardiac myosin in the apo form or bound toOmecamtiv mecarbilorMavacamten. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.

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