Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness - Compartimentation et dynamique cellulaires Accéder directement au contenu
Article Dans Une Revue Cell Année : 2020

Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness

Máté Gyimesi
  • Fonction : Auteur
Ádám Horváth
  • Fonction : Auteur
Demeter Túrós
  • Fonction : Auteur
Sharad Kumar Suthar
Máté Pénzes
  • Fonction : Auteur
Csilla Kurdi
  • Fonction : Auteur
Carlos Kikuti
Kathleen Ruppel
  • Fonction : Auteur
Darshan Trivedi
  • Fonction : Auteur
James Spudich
  • Fonction : Auteur
István Lőrincz
  • Fonction : Auteur
Anna Á. Rauscher
Mihály Kovács
  • Fonction : Auteur
Endre Pál
  • Fonction : Auteur
Anne Houdusse

Résumé

Muscle spasticity after nervous system injuries and painful low back spasm affect more than 10% of global population. Current medications are of limited efficacy and cause neurological and cardiovascular side effects because they target upstream regulators of muscle contraction. Direct myosin inhibition could provide optimal muscle relaxation; however, targeting skeletal myosin is particularly challenging because of its similarity to the cardiac isoform. We identified a key residue difference between these myosin isoforms, located in the communication center of the functional regions, which allowed us to design a selective inhibitor, MPH-220. Mutagenic analysis and the atomic structure of MPH-220-bound skeletal muscle myosin confirmed the mechanism of specificity. Targeting skeletal muscle myosin by MPH-220 enabled muscle relaxation, in human and model systems, without cardiovascular side effects and improved spastic gait disorders after brain injury in a disease model. MPH-220 provides a potential nervous-system-independent option to treat spasticity and muscle stiffness
Fichier principal
Vignette du fichier
Gyimesi et al revised manuscript Cell rs.pdf (5.25 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03453772 , version 1 (29-11-2021)

Identifiants

Citer

Máté Gyimesi, Ádám Horváth, Demeter Túrós, Sharad Kumar Suthar, Máté Pénzes, et al.. Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness. Cell, 2020, 183 (2), pp.335-346.e13. ⟨10.1016/j.cell.2020.08.050⟩. ⟨hal-03453772⟩
91 Consultations
35 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More