Switch‐Peptide in statu nascendi: Induktion von Konformationsübergängen und deren Bedeutung in degenerativen Erkrankungen

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).…”

“…In the S off state (pH 4.5, 50 mm acetate, 150 mm NaCl) and at concentrations between 10-100 mm, the CD spectrum of peptide I displays the Cotton effect which is typical of a b-sheet structure (curve 1 in Figure 2 A). Activation of the helixinducing Ncap (S on ) through a pH-induced O!N acyl group migration [9,11] is not sufficiently strong to overcome the intrinsic b-sheet propensity of Ab(14-25), thus resulting in identical CD spectra. However, when the Ncap was activated in the presence of 25 % 2,2,2-trifluoroethanol (TFE) as a cosolvent to promote the a-helix, we observed an unprecedented transition from a predominantly b-sheet structure in the S off state (curve 1 and 2) to a predominantly a-helix structure in the S on state (curve 3) that was complete in less than five minutes at room temperature (t 1/2 = 150 s, inset in Figure 2 A).…”

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

“…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.…”