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Mbianda Bakail ChemRxiv_full_OK.pdf (4.65 MB)

Optimal Anchoring of a Urea-based Foldamer Inhibitor of ASF1 Histone Chaperone Through Backbone Plasticity

preprint
submitted on 08.07.2020, 14:32 and posted on 09.07.2020, 10:12 by Johanne Mbianda, May Bakail, Christophe André, Gwenaëlle Moal, Marie E. Perrin, Raphaël Guerois, François Becher, Pierre Legrand, Seydou Traore, Céline Douat, Gilles GUICHARD, Francoise OCHSENBEIN

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 significantly 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 striking 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 non-peptide oligourea segments is the resistance to proteolysis in human plasma which was highly improved compared to the cognate α-helical peptide.

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, the Synchrothron Soleil. The project was supported by the ANR 2007 BREAKABOUND, 2011 BIPBIP, 2012 CHAPINHIB, 2015 CHIPSET, 2015 CHIMPP2I and the program labeled by the ARC foundation 2016. M.B. was supported by Canceropole (Paris, France), and a grant for young researchers from La Ligue contre le Cancer. J.B. was supported by La Ligue contre le Cancer.

History

Email Address of Submitting Author

francoise.ochsenbein@cea.fr

Institution

CEA, CNRS, Univ Paris-Saclay

Country

France

ORCID For Submitting Author

0000-0002-9027-4384

Declaration of Conflict of Interest

Authors declare no competing interests

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