Switch-Peptides: From Conformational Studies to Alzheimer's Disease

Abstract

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.

Disruption of Amyloid‐Derived Peptide Assemblies through the Controlled Induction of a β‐Sheet to α‐Helix Transformation: Application of the Switch Concept

“…Furthermore, flexibility in the incorporation of multiple, orthogonally protected switch elements, which can be triggered in a selective and specific manner by using chemical, enzymatic, and/or photolytic procedures, [8][9][10] could open new possibilities in protein engineering and the design of "smart" materials with tunable structural, functional, and physiochemical properties.…”

“…Despite the stability of bsheet-rich amyloid fibrils against proteases, acids, and chemical denaturants, increasing evidence from human [4] and in vitro studies indicates that a dynamic structure exists within amyloid fibrils and suggests that the process of amyloid formation is reversible. [5a,b] These findings, along with the fact that strategies aimed at the destabilization of amyloid fibrils and/or the acceleration of their clearance seem to reverse the disease phenotype, [6][7] suggest that a detailed understanding of the stability and dynamic behavior of amyloid fibrils is of critical importance to the development of therapeutic strategies for amyloid diseases.Our research group has previously shown [8][9][10] that the incorporation of molecular switches into polypeptides, based on an in situ intramolecular O!N acyl group migration, [11] allows for the controlled induction or reversal of secondary structural transitions [12a,b,c] and self-assembly of small peptide chains. Herein we describe a switch peptide that is designed to disrupt amyloid-like b-sheet assemblies through the controlled induced transition from a b-sheet to an a-helix structure (Figure 1).…”

“…Our research group has previously shown [8][9][10] that the incorporation of molecular switches into polypeptides, based on an in situ intramolecular O!N acyl group migration, [11] allows for the controlled induction or reversal of secondary structural transitions [12a,b,c] and self-assembly of small peptide chains. Herein we describe a switch peptide that is designed to disrupt amyloid-like b-sheet assemblies through the controlled induced transition from a b-sheet to an a-helix structure (Figure 1).…”

Switch‐Peptides: Design and Characterization of Controllable Super‐Amyloid‐Forming Host–Guest Peptides as Tools for Identifying Anti‐Amyloid Agents

“…N acyl migration. [5][6][7][8][9][10][11][12][13][14][15][16] However, because of the special synthetic and purification skills required to prepare the full-length Ab switch-peptides, such peptides are not suitable for use in highthroughput screening assays. Therefore, the development of reliable model systems that are readily accessible and adaptable to automated HTS is of particular interest to understanding the mechanism of amyloid formation and facilitating the discovery of aggregation inhibitors of Ab and other amyloid-forming proteins.…”

“…Previously, we [5][6][7][8] and others [9][10][11][12] have shown that various steps along the amyloid formation pathway, including peptide/ protein misfolding, self-assembly, and amyloid formation and disassembly, can be triggered in a highly controllable manner through the incorporation of molecular switches into the amyloid-forming polypeptides, based on in situ intramolecular O! N acyl migration.…”