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Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis

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-p38MAP...

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Autores principales: Vattathara, Jane Jose, Prakash, Ohm, Subhramanian, Sunitha, Satheeshkumar, Madathiparambil Kumaran, Xavier, Tessy, Anil, Meenakshi, Pillai, Gopal S., Anandakuttan, Anandkumar, Radhakrishnan, Sureshkumar, Sivanarayanan, T. B., AKK, Unni, Mohan, Chethampadi Gopi, Menon, Krishnakumar N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051966/
https://www.ncbi.nlm.nih.gov/pubmed/32123210
http://dx.doi.org/10.1038/s41598-020-60710-2
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author Vattathara, Jane Jose
Prakash, Ohm
Subhramanian, Sunitha
Satheeshkumar, Madathiparambil Kumaran
Xavier, Tessy
Anil, Meenakshi
Pillai, Gopal S.
Anandakuttan, Anandkumar
Radhakrishnan, Sureshkumar
Sivanarayanan, T. B.
AKK, Unni
Mohan, Chethampadi Gopi
Menon, Krishnakumar N.
author_facet Vattathara, Jane Jose
Prakash, Ohm
Subhramanian, Sunitha
Satheeshkumar, Madathiparambil Kumaran
Xavier, Tessy
Anil, Meenakshi
Pillai, Gopal S.
Anandakuttan, Anandkumar
Radhakrishnan, Sureshkumar
Sivanarayanan, T. B.
AKK, Unni
Mohan, Chethampadi Gopi
Menon, Krishnakumar N.
author_sort Vattathara, Jane Jose
collection PubMed
description 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.
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spelling pubmed-70519662020-03-06 Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis Vattathara, Jane Jose Prakash, Ohm Subhramanian, Sunitha Satheeshkumar, Madathiparambil Kumaran Xavier, Tessy Anil, Meenakshi Pillai, Gopal S. Anandakuttan, Anandkumar Radhakrishnan, Sureshkumar Sivanarayanan, T. B. AKK, Unni Mohan, Chethampadi Gopi Menon, Krishnakumar N. Sci Rep Article 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. Nature Publishing Group UK 2020-03-02 /pmc/articles/PMC7051966/ /pubmed/32123210 http://dx.doi.org/10.1038/s41598-020-60710-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Vattathara, Jane Jose
Prakash, Ohm
Subhramanian, Sunitha
Satheeshkumar, Madathiparambil Kumaran
Xavier, Tessy
Anil, Meenakshi
Pillai, Gopal S.
Anandakuttan, Anandkumar
Radhakrishnan, Sureshkumar
Sivanarayanan, T. B.
AKK, Unni
Mohan, Chethampadi Gopi
Menon, Krishnakumar N.
Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis
title Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis
title_full Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis
title_fullStr Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis
title_full_unstemmed Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis
title_short Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis
title_sort substrate specific inhibitor designed against the immunomodulator gmf-beta reversed the experimental autoimmune encephalomyelitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051966/
https://www.ncbi.nlm.nih.gov/pubmed/32123210
http://dx.doi.org/10.1038/s41598-020-60710-2
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