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

Abstract

-Sheet-based assemblies have attracted a considerable amount of attention from researchers of various disciplines because of their association with a variety of diseases and their emerging potential in material sciences and biotechnology. [1] Protein misfolding and self-assembly into highly ordered b-sheet-rich fibrillar assemblies that are known as amyloid fibrils are common features of a growing class of systemic and neurodegenerative diseases, which include Alzheimer s, Parkinson s, and Huntington s diseases, senile systemic amyloidoses, as well as type II diabetes. [2] Although there is strong evidence that implicates amyloid formation in the pathogenesis of these diseases, the precise mechanisms of amyloid formation and clearance in vivo, as well as the structural basis of amyloid toxicity, remain unknown. The lack of tools to monitor and/or control the initial structural transitions associated with protein misfolding, amyloid formation, and/or dissociation is the main cause of this gap in knowledge. Significant efforts have been devoted to study proteins and small peptides that self-assemble into amyloidlike fibrillar structures as model systems to investigate amyloid formation or to generate materials with interesting physical properties. However, knowledge of the mechanical and structural dynamics within b-sheet assemblies such as amyloid fibrils remains limited. Early assumptions that bsheet assemblies, which include amyloid fibrils, occupy a global minimum of free energy that is lower than that of the native state [3] led to a greater emphasis on the understanding and inhibition of amyloid formation, rather than that of amyloid dissociation and clearance. 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). The experimental results illustrate the potential of switch peptides as a tool to investigate the structural dynamics of amyloid fibrils, to provide an insight into the structural basis o...

Aggregation Induced α-Helix/β-Sheet Transition of the Poly(ethylene glycol)-attached Peptide

“…As plotted in Figure 3a, the molar ellipticity differences at 208 and 215 nm (½ 208 =½ 215 ) as a ratio of -helix/-sheet content decreased gradually. The transition from -helix to -sheet was completed within 4 h. Peptide moiety having no PEG chain; H 2 N-(LELL) 4 was separately prepared and the secondary structure in aqueous solvent at pH 3.0 was monitored by CD spectrum. It showed stable -helix even after incubating for 24 h (Figure 3b).…”

“…The observed transition of secondary structure was also influenced by N-terminus structure of the peptide segment. The acetylated moiety at N-terminus amino group of the peptide segment, Ac-(LELL) 4 -PEG, showed a stable -helix at pH 3.0 as plotted in Figure 3d. From these results, it was indicated that the observed -helix/-sheet transition of H 2 N-(LELL) 4 -PEG at pH 3.0 was governed either by the charge state of N-terminus group and side chain of the peptide segment.…”

“…[1][2][3] One of the most contributive features of peptides for these applications would be the transition ability of secondary structure such as -helix/random coil, random coil/ -sheet, and -helix/-sheet transition. [4][5][6][7][8][9] Especially, thesheet structure often provides unique self-assembled objects such as fibrils, ribbons, and barrels based on inter-strand hydrogen bonding. [10][11][12][13][14][15] Amphiphilic block copolymer is another attractive building block for self-assembled nano-architecture.…”

Medicinal Chemistry Focusing on Aggregation of Amyloid-β

“…[34][35][36][37][38][39][40] Thus, the O-acyl isopeptide can serve as a means to mask the function of the parent peptide temporarily, which can then be regained by triggering the Oto-N acyl migration. Molecular mechanisms of amyloid formation, [34][35][36]39) Youhei Sohma and stromal cell-derived factor-1α 40) were studied using the corresponding O-acyl precursors. Moreover, the O-acyl isopeptide unit was incorporated as a part of functional peptides, which can control the intracellular localization of a target molecule 41) and protein splicing to regulate protein catalysis.…”

pH-Induced Morphological Change of Molecular Membrane Composed of Amphiphilic Polypeptide-Poly(ethylene glycol) Diblock Copolymer at Air/Water Interface

“…Souhei ABIKO 1 , Masayoshi TANAKA 1 , and Takatoshi KINOSHITA 1  1 Graduate School of Engineering, Nagoya Institute of Technology (Gokiso-cho, Showa-ku, Nagoya 466 8555, Japan) The monolayer constructed by diblock copolymers at an air/water interface was studied for two-dimensional nano patterning. A pH-sensitive polypeptide-poly(ethylene glycol) diblock copolymer, (LELL) 4 -PEG, was synthesized and the monolayers of (LELL) 4 -PEG formed an air/water interface.…”