Optimal anchoring of a foldamer inhibitor of ASF1 histone chaperone through backbone plasticity

Mbianda J, Bakail MM, André C, Moal G, Perrin ME, Pinna G, Guerois R, Becher F, Legrand P, Traoré S, Douat C, Guichard G, Ochsenbein F. 2021. Optimal anchoring of a foldamer inhibitor of ASF1 histone chaperone through backbone plasticity. Science Advances. 7(12), eabd9153.

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Journal Article | Published | English
Author
Mbianda, Johanne; Bakail, MayIST Austria; André, Christophe; Moal, Gwenaëlle; Perrin, Marie E.; Pinna, Guillaume; Guerois, Raphaël; Becher, Francois; Legrand, Pierre; Traoré, Seydou; Douat, Céline; Guichard, Gilles
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Department
Abstract
Sequence-specific oligomers with predictable folding patterns, i.e., foldamers, provide new opportunities to mimic α-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may notably contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as α helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a notable plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with nonpeptide oligourea segments is the resistance to proteolysis in human plasma, which was highly improved compared to the cognate α-helical peptide.
Publishing Year
Date Published
2021-03-19
Journal Title
Science Advances
Acknowledgement
We thank the Synchrotron SOLEIL, the European Synchrotron Radiation Facility (ESRF), and the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INBS-05. We are particularly grateful to A. Clavier and A. Campalans for help in setting up and performing the cell penetration assays. Funding: Research was funded by the French Centre National de Recherche Scientifique (CNRS), the Commissariat à l’Energie Atomique (CEA), University of Bordeaux, University Paris-Saclay, and the Synchrotron Soleil. The project was supported by the ANR 2007 BREAKABOUND (JC-07-216078), 2011 BIPBIP (ANR-10-BINF-0003), 2012 CHAPINHIB (ANR-12-BSV5-0022-01), 2015 CHIPSET (ANR-15-CE11-008-01), 2015 HIMPP2I (ANR-15-CE07-0010), and the program labeled by the ARC foundation 2016 PGA1*20160203953). M.B. was supported by Canceropole (Paris, France) and a grant for young researchers from La Ligue contre le Cancer. J.M. was supported by La Ligue contre le Cancer.
Volume
7
Issue
12
Article Number
eabd9153
ISSN
IST-REx-ID

Cite this

Mbianda J, Bakail MM, André C, et al. Optimal anchoring of a foldamer inhibitor of ASF1 histone chaperone through backbone plasticity. Science Advances. 2021;7(12). doi:10.1126/sciadv.abd9153
Mbianda, J., Bakail, M. M., André, C., Moal, G., Perrin, M. E., Pinna, G., … Ochsenbein, F. (2021). Optimal anchoring of a foldamer inhibitor of ASF1 histone chaperone through backbone plasticity. Science Advances. American Association for the Advancement of Science. https://doi.org/10.1126/sciadv.abd9153
Mbianda, Johanne, May M Bakail, Christophe André, Gwenaëlle Moal, Marie E. Perrin, Guillaume Pinna, Raphaël Guerois, et al. “Optimal Anchoring of a Foldamer Inhibitor of ASF1 Histone Chaperone through Backbone Plasticity.” Science Advances. American Association for the Advancement of Science, 2021. https://doi.org/10.1126/sciadv.abd9153.
J. Mbianda et al., “Optimal anchoring of a foldamer inhibitor of ASF1 histone chaperone through backbone plasticity,” Science Advances, vol. 7, no. 12. American Association for the Advancement of Science, 2021.
Mbianda J, Bakail MM, André C, Moal G, Perrin ME, Pinna G, Guerois R, Becher F, Legrand P, Traoré S, Douat C, Guichard G, Ochsenbein F. 2021. Optimal anchoring of a foldamer inhibitor of ASF1 histone chaperone through backbone plasticity. Science Advances. 7(12), eabd9153.
Mbianda, Johanne, et al. “Optimal Anchoring of a Foldamer Inhibitor of ASF1 Histone Chaperone through Backbone Plasticity.” Science Advances, vol. 7, no. 12, eabd9153, American Association for the Advancement of Science, 2021, doi:10.1126/sciadv.abd9153.
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