Skip to Main content Skip to Navigation
Theses

Foldamères stabilisateurs d’hélices peptidiques : Applications à l’inhibition d’interactions protéine-protéine.

Abstract : Α-Helices are key elements of biomolecular recognition, as reflected by the fact that a large fraction of the protein-protein complexes in the Protein Data Bank (PDB) feature helical interfaces. However, short isolated peptide helices are generally only weakly populated in aqueous environment and are sensitive to proteolytic degradation, thus limiting their therapeutic potential. Various chemical approaches have been proposed to increase the helix folding propensity of α-peptides. One strategy is to pre-organize the first amide bonds through the use of a "capping box" or a hydrogen bond surrogate. Recently we became interested by the possibility to interface peptide and foldamer helical backbones in order to develop “block co-foldamers“, to generate new generations of α-helix mimics. In our laboratory, we have developed oligourea foldamers which are organized to form helical structures. The similarities in helix screw sense, pitch, and polarity between the peptide α-helix and the oligourea 2.5-helix suggested that it would be feasible to combine these two backbones. In this thesis, we have shown that the resulting oligourea/α-peptide chimeras form well-defined helical structures in polar organic solvents with the propagation of a continuous intramolecular hydrogen bonding network spanning the entire sequence. These studies provided a rationale for the use of the oligourea backbone which is strongly biased towards helix formation could lead to the development of pre-organized caps for the initial four amide NHs and the final four carbonyl groups of a peptide α-helix. We have therefore studied the influence of short oligourea fragments on the stabilization of model water-soluble peptide sequences in α-helices, leading to the development of the foldamer capping box. This strategy awas pplied for the first time to the design of potent inhibitors of protein/protein interactions (e.g. p53/MDM2).
Document type :
Theses
Complete list of metadatas

Cited literature [401 references]  Display  Hide  Download

https://tel.archives-ouvertes.fr/tel-02502235
Contributor : Abes Star :  Contact
Submitted on : Monday, March 9, 2020 - 9:37:09 AM
Last modification on : Tuesday, March 10, 2020 - 1:36:14 AM

File

MAURAN_LAURA_2017.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-02502235, version 1

Collections

Citation

Laura Mauran. Foldamères stabilisateurs d’hélices peptidiques : Applications à l’inhibition d’interactions protéine-protéine.. Autre. Université de Bordeaux, 2017. Français. ⟨NNT : 2017BORD0908⟩. ⟨tel-02502235⟩

Share

Metrics

Record views

77

Files downloads

168