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.

Several amyloid‐forming proteins are characterized by the presence of hydrophobic and highly amyloidogenic core sequences that play critical roles in the initiation and progression of amyloid fibril formation. Therefore targeting these sequences represents a viable strategy for identifying candidate molecules that could interfere with amyloid formation and toxicity of the parent proteins. However, the highly amyloidogenic and insoluble nature of these sequences has hampered efforts to develop high‐throughput fibrillization assays. Here we describe the design and characterization of host–guest switch peptides that can be used for in vitro mechanistic and screening studies that are aimed at discovering aggregation inhibitors that target highly amyloidogenic sequences. These model systems are based on a host–guest system where the amyloidogenic sequence (guest peptide) is flanked by two β‐sheet‐promoting (Leu‐Ser)n oligomers as host sequences. Two host–guest peptides were prepared by using the hydrophobic core of Aβ comprising residues 14–24 (HQKLVFFAEDV) as the guest peptide with switch elements inserted within (peptide 1) or at the N and C termini of the guest peptide (peptide 2). Both model peptides can be triggered to undergo rapid self‐assembly and amyloid formation in a highly controllable manner and their fibrillization kinetics is tuneable by manipulating solution conditions (for example, peptide concentration and pH). The fibrillization of both peptides reproduces many features of the full‐length Aβ peptides and can be inhibited by known inhibitors of Aβ fibril formation. Our results suggest that this approach can be extended to other amyloid proteins and should facilitate the discovery of small‐molecule aggregation inhibitors and the development of more efficacious anti‐amyloid agents to treat and/or reverse the pathogenesis of neurodegenerative and systemic amyloid diseases.

No abstract