Design on a Rational Basis of High-Affinity Peptides Inhibiting the Histone Chaperone ASF1

Bakail, May; Gaubert, Albane; Andréani, Jessica; Moal, Gwénaëlle; Pinna, Guillaume; Boyarchuk, Ekaterina; Gaillard, Marie-Cécile; Courbeyrette, Régis; Mann, Carl; Thuret, Jean‐Yves; Guichard, Bérengère; Murciano, Brice; Richet, Nicolas; Poitou, Adeline; Frederic, Claire; Du, Marie-Hélène Le; Agez, Morgane; Roelants, Caroline; Gurard-Levin, Zachary A.; Almouzni, Geneviève; Guérois, Raphaël; Ochsenbein, Françoise

doi:10.1016/j.chembiol.2019.09.002

“…In our previous study, we showed that Trp3 combined with the ASTE motif led to a 10-fold increase in the affinity for ASF1. (30) With the aim to further improve apolar contacts with the surface of ASF1, we substituted Trp3 in P3 by a napthylalanine (Nal3 in P4) (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

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

Mbianda¹,

Bakail²,

André³

et al. 2020

Preprint

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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.

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“…2). The binding affinity remained in the (C) Structure of the complex hASF1A(1-156)-ip4 (pdb 6foh) (30). same range as that of P3, but the analysis of the thermodynamic parameters indicated a more favorable contribution to binding entropy (Table 1 and fig.…”

Section: Defining the Minimal Helical Part Required For Asf1 Bindingmentioning

confidence: 96%

“…As in ip4, peptides P1 to P3 contain a Trp in position 3 whose indole side chain enables favorable interactions with the apolar patch in ASF1 formed by Val 92 and Tyr 112 . In our previous study, we showed that Trp 3 combined with the N-terminal capping motif led to a 10-fold increase in the affinity for ASF1 (30). With the aim to further improve apolar contacts with the surface of ASF1, we substituted Trp 3 in P3 by a napthylalanine (Nal 3 in P4) (Fig.…”

Section: Defining the Minimal Helical Part Required For Asf1 Bindingmentioning

confidence: 99%

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

Mbianda

¹

,

Bakail

²

,

André

³

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…( 30) Upon conjugation to a cell-penetrating peptide (CPP), ip4 was able to translocate into cells, impair cell proliferation and perturb the cell cycle progression similarly to the silencing of ASF1. (30) Injection of this conjugate in mouse allografts reduced tumor growth. However, further exploration of its therapeutic potential was early compromised by its sensitivity to protease degradation.…”

Section: Introductionmentioning

confidence: 99%

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

Mbianda¹,

Bakail²,

André³

et al. 2020

Preprint

Self Cite

0

View full text Add to dashboard Cite

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.

show abstract

Design on a Rational Basis of High-Affinity Peptides Inhibiting the Histone Chaperone ASF1

Cited by 15 publications

References 65 publications

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

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

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

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

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