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Issue 93, 2015
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Involvement of covalent interactions in the mode of action of PPARβ/δ antagonists

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Abstract

A broad range of chemical structures modulate the inductive and repressive transcriptional regulation of the peroxisome proliferator-activated receptor β/δ (PPARβ/δ). In order to shed light on mechanistic differences in the modes of action of three classes of the reported PPARβ/δ antagonists, an investigation into their in vitro biological and chemical reactivities, with particular focus on covalent reactivity, was undertaken. The results reported here, substantiate the covalent modification of Cys249 as a part of the mode of action of the 5-trifluoromethyl-2-sulfonylpyridine class of antagonists. In contrast, GSK0660 does not appear to be a covalently binding antagonistic ligand. Additionally, we demonstrate the electrophilic nature of the recently published antagonist DG172 towards thiolates, although a covalent adduct with PPARβ/δ is not detected in our experiments.

Graphical abstract: Involvement of covalent interactions in the mode of action of PPARβ/δ antagonists

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Publication details

The article was received on 05 Aug 2015, accepted on 28 Aug 2015 and first published on 01 Sep 2015


Article type: Paper
DOI: 10.1039/C5RA15707B
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RSC Adv., 2015,5, 76483-76490

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    Involvement of covalent interactions in the mode of action of PPARβ/δ antagonists

    Å. Kaupang, S. Hildonen, T. G. Halvorsen, M. Mortén, A. Vik and T. V. Hansen, RSC Adv., 2015, 5, 76483
    DOI: 10.1039/C5RA15707B

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