Evidence of covalent interaction of fumaric acid esters with sulfhydryl groups in peptides

Abstract

Fumaric acid esters, namely dimethylfumarate, have been used for the treatment of psoriasis for many years. Still, their mode of action is not fully clear. Because addition of nucleophiles to the double bonds of fumarates can occur (Michael analogous addition), a study of the interaction of fumarates with cysteine and cysteine‐containing peptides possessing nucleophilic sulfhydryl group was carried out. Experiments were performed in aqueous medium at pH 7.4 and at 37 °C to simulate physiological conditions. It was proven by mass spectrometric measurements using an ion‐trap and time‐of‐flight instrument that a covalent bond can form between fumarates and the sulfhydryl group of cysteine or cysteinyl residues in peptides. Structures of the interaction products were elucidated by multistage mass spectrometry applying collision‐induced dissociation. Higher reactivity of dimethylfumarate in comparison to monomethylfumarate and fumaric acid was observed. Copyright © 2005 John Wiley & Sons, Ltd.