α‑Linolenic Acid–Valproic Acid Conjugates: Toward Single-Molecule Polypharmacology for Multiple Sclerosis

Multiple sclerosis (MS) is a complex inflammatory, degenerative, and demyelinating disease of the central nervous system. Although treatments exist, MS cannot be cured by available drugs, which primarily target neuroinflammation. Thus, it is feasible that a well concerted polypharmacological approac...

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Published in:ACS medicinal chemistry letters 2020-12, Vol.11 (12), p.2406-2413
Main Authors: Rossi, Michele, Petralla, Sabrina, Protti, Michele, Baiula, Monica, Kobrlova, Tereza, Soukup, Ondrej, Spampinato, Santi Mario, Mercolini, Laura, Monti, Barbara, Bolognesi, Maria Laura
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Language:English
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Summary:Multiple sclerosis (MS) is a complex inflammatory, degenerative, and demyelinating disease of the central nervous system. Although treatments exist, MS cannot be cured by available drugs, which primarily target neuroinflammation. Thus, it is feasible that a well concerted polypharmacological approach able to act at multiple points within the intricate network of inflammation, neurodegeneration, and demyelination/remyelination pathways would succeed where other drugs have failed. Starting from reported beneficial effects of α-linolenic acid (ALA) and valproic acid (VPA) in MS, and by applying a rational strategy, we developed a small set of codrugs obtained by conjugating VPA and ALA through proper linkers. A cellular profiling identified 1 as a polypharmacological tool able not only to modulate microglia polarization, but also to counteract neurodegeneration and demyelination and induce oligodendrocyte precursor cell differentiation, by acting on multiple biochemical and epigenetic pathways.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.0c00375