The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands

Yaochun Xu (1) , Isabelle Correia (2) , Tap Ha-Duong (1) , Nadjib Kihal (1) , Jean-Louis Soulier (1) , Julia Kaffy (1) , Benoît Crousse (1) , Olivier Lequin (2) , Sandrine Ongeri (1)

1 BioCIS - Biomolécules : Conception, Isolement, Synthèse
2 LBM UMR 7203 - Laboratoire des biomolécules

Pentapeptides having the sequence R-HN-Ala-Val-X-Val-Leu-OMe, where the central residue X is L-serine, L-threonine, (2S,3R)-L-CF 3-threonine and (2S,3S)-L-CF 3-threonine were prepared. The capacity of (2S,3S)-and (2S,3R)-CF 3-threonine analogues to stabilize an extended structure when introduced in the central position of pentapeptides is demonstrated by NMR conformational studies and molecular dynamics simulations. CF 3-threonine containing pentapeptides are more prone to mimic β-strands than their natural Ser and Thr pentapeptide analogues. The proof of concept that these fluorinated β-strand mimics are able to disrupt protein–protein interactions involving β-sheet structures is provided. The CF 3-threonine containing pentapeptides interact with the amyloid peptide Aβ 1-42 in order to reduce the protein–protein interactions mediating its aggregation process.

Mots clés: aggregation; beta-sheet; fluorine; peptide; unnatural amino acid; aggregation

Domaines: Chimie organique

Yaochun Xu, Isabelle Correia, Tap Ha-Duong, Nadjib Kihal, Jean-Louis Soulier, et al.. The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands. Beilstein Journal of Organic Chemistry, 2017, 13, pp.2842 - 2853. ⟨10.3762/bjoc.13.276⟩. ⟨hal-01700974⟩