Proteolytically Stable Diaza-Peptide Foldamers Mimic Helical Hot Spots of Protein–Protein Interactions and Act as Natural Chaperones

A novel class of peptidomimetic foldamers based on diaza-peptide
units are reported. Circular dichroism, attenuated total reflection
–Fourier transform infrared, NMR, and molecular dynamics studies
demonstrate that unlike the natural parent nonapeptide, the specific
incorporation of one diaza-peptide unit at the N-terminus allows helical
folding in water, which is further reinforced by the introduction
of a second unit at the C-terminus. The ability of these foldamers
to resist proteolysis, to mimic the small helical hot spot of transthyretin-amyloid
β (Aβ) cross-interaction, and to decrease pathological
Aβ aggregation demonstrates that the introduction of diaza-peptide
units is a valid approach for designing mimics or inhibitors of protein–protein
interaction and other therapeutic peptidomimetics. This study also
reveals that small peptide foldamers can play the same role as physiological
chaperone proteins and opens a new way to design inhibitors of amyloid
protein aggregation, a hallmark of more than 20 serious human diseases
such as Alzheimer’s disease.