Switch-peptides as folding precursors in self-assembling peptides and amyloid fibrillogenesis

The study of conformational transitions of peptides has obtained considerable attention recently because of their importance as a mol. key event in a variety of degenerative diseases. However, the study of peptide self-assembly into beta-sheets and amyloid beta (Abeta) fibrils is strongly hampered by their difficult synthetic access and low soly. We have recently developed a new concept termed "switch-peptides" that allows the controlled onset of polypeptide folding and misfolding at physiol. conditions. As a major feature, the folding process is initiated by chem. or enzyme triggered O,N-acyl migration in flexible and sol. folding precursors contg. Ser- or Thr-derived switch (S)-elements. The elaborated methodologies are exemplified for the in situ conversion of NPY- and Cyclosporine A-derived prodrugs, as well as for the onset and reversal of alpha and beta conformational transitions in Abeta peptides. In combining orthogonally addressable switch-elements, the consecutive switching on of S-elements gives new insights into the role of individual peptide segments ("hot spots") in early processes of polypeptide self-assembly and fibrillogenesis. Finally, the well-known secondary structure disrupting effect of pseudoprolines (Psi Pro) is explored for its use as a building block (S-element) in switch-peptides. To this end, synthetic strategies are described, allowing for the prepn. of Psi Pro-contg. folding precursors, exhibiting flexible random-coil conformations devoid of fibril forming propensity. The onset of beta-sheet and fibril formation by restoring the native peptide chain in a single step classify Psi Pro-units as the most powerful tool for inhibiting peptide self-assembly, and complement the present methodologies of the switch-concept for the study of fibrillogenesis.