Isolevuglandins as mediators of disease and the development of dicarbonyl scavengers as pharmaceutical interventions.

Davies SS, May-Zhang LS, Boutaud O, Amarnath V, Kirabo A, Harrison DG
Pharmacol Ther. 2020 205: 107418

PMID: 31629006 · PMCID: PMC7495735 · DOI:10.1016/j.pharmthera.2019.107418

Products of lipid peroxidation include a number of reactive lipid aldehydes such as malondialdehyde, 4-hydroxy-nonenal, 4-oxo-nonenal, and isolevuglandins (IsoLGs). Although these all contribute to disease processes, the most reactive are the IsoLGs, which rapidly adduct to lysine and other cellular primary amines, leading to changes in protein function, cross-linking and immunogenicity. Their rapid reactivity means that only IsoLG adducts, and not the unreacted aldehyde, can be readily measured. This high reactivity also makes it challenging for standard cellular defense mechanisms such as aldehyde reductases and oxidases to dispose of them before they react with proteins and other cellular amines. This led us to seek small molecule primary amines that might trap and inactivate IsoLGs before they could modify cellular proteins or other endogenous cellular amines such as phosphatidylethanolamines to cause disease. Our studies identified 2-aminomethylphenols including 2-hydroxybenzylamine as IsoLG scavengers. Subsequent studies showed that they also trap other lipid dicarbonyls that react with primary amines such as 4-oxo-nonenal and malondialdehyde, but not hydroxyalkenals like 4-hydroxy-nonenal that preferentially react with soft nucleophiles. This review describes the use of these 2-aminomethylphenols as dicarbonyl scavengers to assess the contribution of IsoLGs and other amine-reactive lipid dicarbonyls to disease and as therapeutic agents.

Copyright © 2019. Published by Elsevier Inc.

MeSH Terms (9)

Aldehydes Amines Animals Benzylamines Drug Development Humans Lipid Peroxidation Lipids Proteins

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