Aspects of conformational transitions, folding, and misfolding of peptides and proteins have moved into the center of interest in various domains of research at the interface of chemistry, biology, and medicine because of their impact on neurodegenerative diseases.[1] For example, recent research suggests that conformational transitions of soluble amyloid b precursor molecules into aggregated, b-sheet-type forms play a key role in the deposition of cerebral amyloid plaques

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.

Studies on designed peptides that exhibit high tendencies for medium-induced conformational transitions have recently attracted much attention because structural changes are considered as molecular key processes in degenerative diseases. The experimental access to these events has been limited so far mainly due to the intrinsic tendency of the involved polypeptides for self-association and aggregation, e.g. amyloid β plaque formation, thought to be at the origin of Alzheimer's disease. We have developed a new concept termed 'switchpeptides' which allows the controlled onset of polypeptide folding and misfolding in vitro and in vivo, starting from a soluble, non-toxic precursor molecule. As a major feature, the folding process is initiated by enzyme-triggered N,O-acyl migrations restoring the native peptide backbone in situ. As the folding is set off in the moment of creating the bioactive molecule ('in statu nascendi', ISN), our concept allows for the first time the investigation of the early steps of protein misfolding as relevant in degenerative diseases, opening new perspectives for the rational design of therapeutically relevant compounds.

No abstract

No abstract