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Allosteric cross-talk in chromatin can mediate drug-drug synergy

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Adhireksan Zenita, Palermo Giulia, Riedel Tina, Ma Zhujun, Muhammad Reyhan, Rothlisberger Ursula, Dyson Paul J., Davey Curt A.,
Project Modulation of the site specificity of binding of metal-based drugs to chromatin
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Original article (peer-reviewed)

Journal Nature Communications
Volume (Issue) 8
Page(s) 14860 - 14860
Title of proceedings Nature Communications
DOI 10.1038/ncomms14860

Abstract

Exploitation of drug–drug synergism and allostery could yield superior therapies by capita- lizing on the immensely diverse, but highly specific, potential associated with the biological macromolecular landscape. Here we describe a drug–drug synergy mediated by allosteric cross-talk in chromatin, whereby the binding of one drug alters the activity of the second. We found two unrelated drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing cancer cells, which coincides with a substantially greater number of chromatin adducts formed by one of the compounds when adducts from the other agent are also present. We show that this occurs through an allosteric mechanism within the nucleosome, whereby defined histone adducts of one drug promote reaction of the other drug at a distant, specific histone site. This opens up possibilities for epigenetic targeting and suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions.
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