Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning.
Stefania OllaMaristella SteriAlessia FormatoMichael Bernard WhalenSilvia CorbisieroCristina AgrestiPublished in: Pharmaceutics (2021)
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.
Keyphrases
- multiple sclerosis
- oxidative stress
- mass spectrometry
- genome wide
- white matter
- ms ms
- ischemia reperfusion injury
- diabetic rats
- drug induced
- dna damage
- endothelial cells
- protein kinase
- induced apoptosis
- dna methylation
- copy number
- signaling pathway
- emergency department
- gene expression
- transcription factor
- cerebral ischemia
- reactive oxygen species
- induced pluripotent stem cells
- pi k akt
- adverse drug
- anti inflammatory
- molecular dynamics simulations