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

Pentapeptides having the sequence R-HN-Ala-Val- -Val-Leu-OMe, where the central residue is L-serine, L-threonine, (2 ,3 )-L-CF -threonine and (2 ,3 )-L-CF -threonine were prepared. The capacity of (2 ,3 )- and (2 ,3 )-CF -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 -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 -threonine containing pentapeptides interact with the amyloid peptide Aβ in order to reduce the protein-protein interactions mediating its aggregation process.