ABSTRACT
The study of conformational transitions of peptides has obtained considerable attention recently because of their importance as a molecular 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 solubility. We have recently developed a new concept termed switch-peptides that allows the controlled onset of polypeptide folding and misfolding at physiologic conditions. As a major feature, the folding process is initiated by chemically or enzyme triggered O,N-acyl migration in flexible and soluble folding precursors containing 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 (PsiPro) is explored for its use as a building block (S-element) in switch-peptides. To this end, synthetic strategies are described, allowing for the preparation of PsiPro-containing 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 PsiPro-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.
Subject(s)
Amyloid/chemistry , Peptides/chemistry , Amyloid/ultrastructure , Microscopy, Electron , Models, Biological , Models, Molecular , Proline/analogs & derivatives , Proline/chemistry , Protein Folding , Protein Precursors/chemistry , Protein Precursors/ultrastructure , Protein Structure, Secondary , Thiazoles/chemistryABSTRACT
The sequential triggering (Soff --> Son) of O, N-acyl migrations (AcM) by chemical and enzymatic methods (Ti) in peptides containing structure-disrupting switch-elements, S (switch-peptides), offers a novel tool for studying in statu nascendi the onset and inhibition of polypeptide folding and self-assembly as a key process in degenerative diseases.