Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis.
Amino Acid Motifs
Animals
Drug Design
Encephalomyelitis, Autoimmune, Experimental
/ drug therapy
Female
Glia Maturation Factor
/ chemistry
Humans
Immunologic Factors
/ chemistry
Mice, Inbred C57BL
Multiple Sclerosis
/ drug therapy
Phosphorylation
/ drug effects
Small Molecule Libraries
/ administration & dosage
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
02 03 2020
02 03 2020
Historique:
received:
19
08
2019
accepted:
14
02
2020
entrez:
4
3
2020
pubmed:
4
3
2020
medline:
15
12
2020
Statut:
epublish
Résumé
The concept of substrate inhibition to prevent its phosphorylation has potential in drug discovery and is envisioned to treat the autoimmune disorder multiple sclerosis (MS). Glia maturation factor-β (GMF-β) Ser83 phosphorylation by protein kinase A (PKA) is pivotal in the activation of GMF-β-p38MAPK-NFκB biochemical pathway towards proinflammatory response induction in experimental autoimmune encephalomyelitis (EAE). Using structure-based drug design, we identified the small molecule inhibitor 1-H-indazole-4yl methanol (GMFBI.1) that specifically blocked Ser83 phosphorylation site on GMF-β substrate. Using in vitro and in vivo techniques, molecular mechanism of action of GMFBI.1's direct interaction with GMF-β substrate and prevention of its Ser83 phosphorylation was established. GMFBI.1 down regulated p38MAPK phosphorylation and NFκB expression essential for proinflammatory response. Further, GMFBI.1 administration at peak of EAE reversed clinical symptoms, immunopathology, proinflammatory cytokine response and up regulated the anti-inflammatory cytokines. Present strategy of substrate inhibition against the key immunomodulatory target has immense therapeutic potential in MS.
Identifiants
pubmed: 32123210
doi: 10.1038/s41598-020-60710-2
pii: 10.1038/s41598-020-60710-2
pmc: PMC7051966
doi:
Substances chimiques
Glia Maturation Factor
0
Immunologic Factors
0
Small Molecule Libraries
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3790Références
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