Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness.
Adult
Animals
Cardiac Myosins
/ genetics
Cell Line
Drug Delivery Systems
Female
Humans
Male
Mice
Muscle Contraction
/ physiology
Muscle Fibers, Skeletal
/ physiology
Muscle Spasticity
/ genetics
Muscle, Skeletal
/ metabolism
Myosins
/ drug effects
Protein Isoforms
Rats
Rats, Wistar
Skeletal Muscle Myosins
/ drug effects
artificial intelligence
blebbistatin
crystallography
deep learning
force
motor protein
musculoskeletal disorder
sarcomere
stroke
unmet medical need
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
15 10 2020
15 10 2020
Historique:
received:
23
05
2020
revised:
24
07
2020
accepted:
27
08
2020
pubmed:
10
10
2020
medline:
14
5
2021
entrez:
9
10
2020
Statut:
ppublish
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.
Identifiants
pubmed: 33035452
pii: S0092-8674(20)31138-7
doi: 10.1016/j.cell.2020.08.050
pmc: PMC7596007
mid: NIHMS1634063
pii:
doi:
Substances chimiques
Protein Isoforms
0
Cardiac Myosins
EC 3.6.1.-
Skeletal Muscle Myosins
EC 3.6.1.-
Myosins
EC 3.6.4.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
335-346.e13Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM033289
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117138
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
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.