Allosteric cross-talk in chromatin can mediate drug-drug synergy
Exploitation of drug–drug synergism and allostery could yield superior therapies by capitalizing 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, wher...
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sg-ntu-dr.10356-870272023-02-28T16:56:37Z Allosteric cross-talk in chromatin can mediate drug-drug synergy Adhireksan, Zenita Palermo, Giulia Riedel, Tina Ma, Zhujun Muhammad, Reyhan Rothlisberger, Ursula Dyson, Paul J. Davey, Curtis Alexander School of Biological Sciences NTU Institute of Structural Biology Drug Chromatin Exploitation of drug–drug synergism and allostery could yield superior therapies by capitalizing 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. MOE (Min. of Education, S’pore) NMRC (Natl Medical Research Council, S’pore) Published version 2018-01-09T01:33:51Z 2019-12-06T16:33:26Z 2018-01-09T01:33:51Z 2019-12-06T16:33:26Z 2017 Journal Article Adhireksan, Z., Palermo, G., Riedel, T., Ma, Z., Muhammad, R., Rothlisberger, U., et al. (2017). Allosteric cross-talk in chromatin can mediate drug-drug synergy. Nature Communications, 8, 14860-. https://hdl.handle.net/10356/87027 http://hdl.handle.net/10220/44277 10.1038/ncomms14860 en Nature Communications © 2017 The Author(s) (Nature Publishing Group). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ 11 p. application/pdf |
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Drug Chromatin Adhireksan, Zenita Palermo, Giulia Riedel, Tina Ma, Zhujun Muhammad, Reyhan Rothlisberger, Ursula Dyson, Paul J. Davey, Curtis Alexander Allosteric cross-talk in chromatin can mediate drug-drug synergy |
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Exploitation of drug–drug synergism and allostery could yield superior therapies by capitalizing 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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School of Biological Sciences |
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School of Biological Sciences Adhireksan, Zenita Palermo, Giulia Riedel, Tina Ma, Zhujun Muhammad, Reyhan Rothlisberger, Ursula Dyson, Paul J. Davey, Curtis Alexander |
format |
Article |
author |
Adhireksan, Zenita Palermo, Giulia Riedel, Tina Ma, Zhujun Muhammad, Reyhan Rothlisberger, Ursula Dyson, Paul J. Davey, Curtis Alexander |
author_sort |
Adhireksan, Zenita |
title |
Allosteric cross-talk in chromatin can mediate drug-drug synergy |
title_short |
Allosteric cross-talk in chromatin can mediate drug-drug synergy |
title_full |
Allosteric cross-talk in chromatin can mediate drug-drug synergy |
title_fullStr |
Allosteric cross-talk in chromatin can mediate drug-drug synergy |
title_full_unstemmed |
Allosteric cross-talk in chromatin can mediate drug-drug synergy |
title_sort |
allosteric cross-talk in chromatin can mediate drug-drug synergy |
publishDate |
2018 |
url |
https://hdl.handle.net/10356/87027 http://hdl.handle.net/10220/44277 |
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1759854771966050304 |