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

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE
    • Publication Information:
      Publication: Cambridge, Ma : Cell Press
      Original Publication: Cambridge, MIT Press.
    • Subject Terms:
      Muscle, Skeletal/*metabolism ; Skeletal Muscle Myosins/*drug effects ; Skeletal Muscle Myosins/*genetics; Adult ; Animals ; Cardiac Myosins/genetics ; Cardiac Myosins/metabolism ; Cell Line ; Drug Delivery Systems ; Female ; Humans ; Male ; Mice ; Muscle Contraction/physiology ; Muscle Fibers, Skeletal/physiology ; Muscle Spasticity/genetics ; Muscle Spasticity/physiopathology ; Muscle, Skeletal/physiology ; Myosins/drug effects ; Myosins/genetics ; Myosins/metabolism ; Protein Isoforms ; Rats ; Rats, Wistar ; Skeletal Muscle Myosins/metabolism
    • 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.
      Competing Interests: Declaration of Interests The authors declare the following competing interests: employment, A.M.-C. and M.G. are owners of Motorpharma, Ltd. and A.Á.R. and M.G. are part-time employed by Motorpharma, Ltd.; related patents, PCT/EP2017/051829, WO/2017/129782, HU1800129A2, PCT/HU2019/050017, WO/2019/202346A2, and WO/2019/202346A3; J.A.S. is a cofounder and member of the scientific advisory boards of Cytokinetics and MyoKardia, biotechnology companies developing small molecules that target the sarcomere for the treatment of various muscle diseases; K.M.R. is on the scientific advisory board at MyoKardia; and J.A.S., D.V.T., and K.M.R. are cofounders of Kainomyx Inc., a biotechnology company focused on developing small molecules to target tropical diseases.
      (Copyright © 2020 Elsevier Inc. All rights reserved.)
    • Grant Information:
      R01 GM033289 United States GM NIGMS NIH HHS; R01 HL117138 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: artificial intelligence; blebbistatin; crystallography; deep learning; force; motor protein; musculoskeletal disorder; sarcomere; stroke; unmet medical need
    • Accession Number:
      0 (Protein Isoforms)
      EC 3.6.1.- (Cardiac Myosins)
      EC 3.6.1.- (Skeletal Muscle Myosins)
      EC 3.6.4.1 (Myosins)
    • Publication Date:
      Date Created: 20201009 Date Completed: 20210513 Latest Revision: 20211016
    • Publication Date:
      20240829
    • Accession Number:
      PMC7596007
    • Accession Number:
      10.1016/j.cell.2020.08.050
    • Accession Number:
      33035452