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

Máté Gyimesi | Zendy; Ádám I. Horváth | Zendy; Demeter Túrós | Zendy; Sharad Kumar Suthar | Zendy; Máté Pénzes | Zendy; Csilla Kurdi | Zendy; Louise Ca | Zendy; Carlos Kikuti | Zendy; Kathleen M. Ruppel | Zendy; Darshan V. Trivedi | Zendy; James A. Spudich | Zendy; István Lőrincz | Zendy; Anna Á. Rauscher | Zendy; Mihály Kovács | Zendy; Endre Pál | Zendy; S. Komoly | Zendy; Anne Houdusse | Zendy; András MálnásiCsizmadia | Zendy

Open Access

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

Author(s) -

Máté Gyimesi,

Ádám I. Horváth,

Demeter Túrós,

Sharad Kumar Suthar,

Máté Pénzes,

Csilla Kurdi,

Louise Ca,

Carlos Kikuti,

Kathleen M. Ruppel,

Darshan V. Trivedi,

James A. Spudich,

István Lőrincz,

Anna Á. Rauscher,

Mihály Kovács,

Endre Pál,

S. Komoly,

Anne Houdusse,

András MálnásiCsizmadia

Publication year - 2020

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2020.08.050

Subject(s) - biology , myosin , skeletal muscle , spasticity , drug , muscle stiffness , stiffness , anatomy , microbiology and biotechnology , pharmacology , physical medicine and rehabilitation , materials science , medicine , composite material

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.

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