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Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning

In multiple sclerosis (MS), oxidative stress (OS) is implicated in the neurodegenerative processes that occur from the beginning of the disease. Unchecked OS initiates a vicious circle caused by its crosstalk with inflammation, leading to demyelination, axonal damage and neuronal loss. The failure o...

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Autores principales: Olla, Stefania, Steri, Maristella, Formato, Alessia, Whalen, Michael B., Corbisiero, Silvia, Agresti, Cristina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8705550/
https://www.ncbi.nlm.nih.gov/pubmed/34959343
http://dx.doi.org/10.3390/pharmaceutics13122064
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author Olla, Stefania
Steri, Maristella
Formato, Alessia
Whalen, Michael B.
Corbisiero, Silvia
Agresti, Cristina
author_facet Olla, Stefania
Steri, Maristella
Formato, Alessia
Whalen, Michael B.
Corbisiero, Silvia
Agresti, Cristina
author_sort Olla, Stefania
collection PubMed
description In multiple sclerosis (MS), oxidative stress (OS) is implicated in the neurodegenerative processes that occur from the beginning of the disease. Unchecked OS initiates a vicious circle caused by its crosstalk with inflammation, leading to demyelination, axonal damage and neuronal loss. The failure of MS antioxidant therapies relying on the use of endogenous and natural compounds drives the application of novel approaches to assess target relevance to the disease prior to preclinical testing of new drug candidates. To identify drugs that can act as regulators of intracellular oxidative homeostasis, we applied an in silico approach that links genome-wide MS associations and molecular quantitative trait loci (QTLs) to proteins of the OS pathway. We found 10 drugs with both central nervous system and oral bioavailability, targeting five out of the 21 top-scoring hits, including arginine methyltransferase (CARM1), which was first linked to MS. In particular, the direction of brain expression QTLs for CARM1 and protein kinase MAPK1 enabled us to select BIIB021 and PEITC drugs with the required target modulation. Our study highlights OS-related molecules regulated by functional MS variants that could be targeted by existing drugs as a supplement to the approved disease-modifying treatments.
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spelling pubmed-87055502021-12-25 Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning Olla, Stefania Steri, Maristella Formato, Alessia Whalen, Michael B. Corbisiero, Silvia Agresti, Cristina Pharmaceutics Article In multiple sclerosis (MS), oxidative stress (OS) is implicated in the neurodegenerative processes that occur from the beginning of the disease. Unchecked OS initiates a vicious circle caused by its crosstalk with inflammation, leading to demyelination, axonal damage and neuronal loss. The failure of MS antioxidant therapies relying on the use of endogenous and natural compounds drives the application of novel approaches to assess target relevance to the disease prior to preclinical testing of new drug candidates. To identify drugs that can act as regulators of intracellular oxidative homeostasis, we applied an in silico approach that links genome-wide MS associations and molecular quantitative trait loci (QTLs) to proteins of the OS pathway. We found 10 drugs with both central nervous system and oral bioavailability, targeting five out of the 21 top-scoring hits, including arginine methyltransferase (CARM1), which was first linked to MS. In particular, the direction of brain expression QTLs for CARM1 and protein kinase MAPK1 enabled us to select BIIB021 and PEITC drugs with the required target modulation. Our study highlights OS-related molecules regulated by functional MS variants that could be targeted by existing drugs as a supplement to the approved disease-modifying treatments. MDPI 2021-12-02 /pmc/articles/PMC8705550/ /pubmed/34959343 http://dx.doi.org/10.3390/pharmaceutics13122064 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Olla, Stefania
Steri, Maristella
Formato, Alessia
Whalen, Michael B.
Corbisiero, Silvia
Agresti, Cristina
Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning
title Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning
title_full Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning
title_fullStr Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning
title_full_unstemmed Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning
title_short Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning
title_sort combining human genetics of multiple sclerosis with oxidative stress phenotype for drug repositioning
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8705550/
https://www.ncbi.nlm.nih.gov/pubmed/34959343
http://dx.doi.org/10.3390/pharmaceutics13122064
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