Abstract：
: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.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Vattathara JJ,Prakash O,Subhramanian S,Satheeshkumar MK,Xavier T,Anil M,Pillai GS,Anandakuttan A,Radhakrishnan S,Sivanarayanan TB,Akk U,Mohan CG,Menon KNdoi
10.1038/s41598-020-60710-2subject
Has Abstractpub_date
2020-03-02 00:00:00pages
3790issue
1issn
2045-2322pii
10.1038/s41598-020-60710-2journal_volume
10pub_type
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