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

Autor:	Gyimesi M; 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., Horváth ÁI; MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary., Túrós D; MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary., Suthar SK; MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary; Printnet, Ltd., Kisgömb utca 25-27, 1135 Budapest, Hungary., Pénzes M; MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary., Kurdi C; MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary., Canon L; Structural Motility, Institut Curie, Paris Université Sciences et Lettres, Sorbonne Université, CNRS UMR144, 75005 Paris, France., Kikuti C; Structural Motility, Institut Curie, Paris Université Sciences et Lettres, Sorbonne Université, CNRS UMR144, 75005 Paris, France., Ruppel KM; Department of Biochemistry, Stanford University School of Medicine, Beckman Center B400, 279 W. Campus Drive, Stanford, CA 94305, USA., Trivedi DV; Department of Biochemistry, Stanford University School of Medicine, Beckman Center B400, 279 W. Campus Drive, Stanford, CA 94305, USA., Spudich JA; Department of Biochemistry, Stanford University School of Medicine, Beckman Center B400, 279 W. Campus Drive, Stanford, CA 94305, USA., Lőrincz I; Printnet, Ltd., Kisgömb utca 25-27, 1135 Budapest, Hungary., Rauscher AÁ; MTA-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary; Motorpharma, Ltd., Szilágyi Erzsébet fasor 27, 1026 Budapest, Hungary., Kovács M; 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., Pál E; Department of Neurology, University of Pécs, Rét utca 2, 7623 Pécs, Hungary., Komoly S; Department of Neurology, University of Pécs, Rét utca 2, 7623 Pécs, Hungary., Houdusse A; Structural Motility, Institut Curie, Paris Université Sciences et Lettres, Sorbonne Université, CNRS UMR144, 75005 Paris, France., Málnási-Csizmadia A; 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.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2020 Oct 15; Vol. 183 (2), pp. 335-346.e13. Date of Electronic Publication: 2020 Oct 08.
DOI:	10.1016/j.cell.2020.08.050
Abstrakt:	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.)
Databáze:	MEDLINE
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