2. Academic Validation
  3. Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness

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

  • Cell. 2020 Oct 15;183(2):335-346.e13. doi: 10.1016/j.cell.2020.08.050.
Máté Gyimesi 1,  Ádám I Horváth 2,  Demeter Túrós 2,  Sharad Kumar Suthar 3,  Máté Pénzes 2,  Csilla Kurdi 2,  Louise Canon 4,  Carlos Kikuti 4,  Kathleen M Ruppel 5,  Darshan V Trivedi 5,  James A Spudich 5,  István Lőrincz 6,  Anna Á Rauscher 7,  Mihály Kovács 8,  Endre Pál 9,  Sámuel Komoly 9,  Anne Houdusse 4,  András Málnási-Csizmadia 10
Affiliations

Affiliations

  • 1 MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary; Motorpharma, Ltd., Szilágyi Erzsébet fasor 27, 1026 Budapest, Hungary. Electronic address: mate.gyimesi@elte.hu.
  • 2 MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary.
  • 3 MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary; Printnet, Ltd., Kisgömb utca 25-27, 1135 Budapest, Hungary.
  • 4 Structural Motility, Institut Curie, Paris Université Sciences et Lettres, Sorbonne Université, CNRS UMR144, 75005 Paris, France.
  • 5 Department of Biochemistry, Stanford University School of Medicine, Beckman Center B400, 279 W. Campus Drive, Stanford, CA 94305, USA.
  • 6 Printnet, Ltd., Kisgömb utca 25-27, 1135 Budapest, Hungary.
  • 7 MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary; Motorpharma, Ltd., Szilágyi Erzsébet fasor 27, 1026 Budapest, Hungary.
  • 8 MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary; Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary and Brunszvik u. 2, 2462 Martonvásár, Hungary.
  • 9 Department of Neurology, University of Pécs, Rét utca 2, 7623 Pécs, Hungary.
  • 10 MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary; Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary and Brunszvik u. 2, 2462 Martonvásár, Hungary. Electronic address: malna@elte.hu.
PMID: 33035452 DOI: 10.1016/j.cell.2020.08.050
Abstract

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.

Keywords

artificial intelligence; blebbistatin; crystallography; deep learning; force; motor protein; musculoskeletal disorder; sarcomere; stroke; unmet medical need.

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