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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8705550 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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