“Click Peptide” Based on the “O-Acyl Isopeptide Method”:  Control of Aβ1−42 Production from a Photo-Triggered Aβ1−42 Analogue

Abstract

A clear understanding of the dynamic events of amyloid beta peptide (Abeta) 1-42, such as the folding, self-assembly, and aggregation processes, would be of great significance in Alzheimer's disease (AD) research. However, elucidation of these Abeta1-42 dynamic events is a difficult issue due to uncontrolled polymerization, which also poses a significant obstacle for establishing an experimental system that clarifies the pathological function of Abeta1-42. On the basis of the O-acyl isopeptide method, we herein developed a novel photo-triggered "click peptide" of Abeta1-42, for example, 26-N-Nvoc-26-AIAbeta42, in which the photocleavable 6-nitroveratryloxycarbonyl (Nvoc) group was introduced at the alpha-amino group of Ser26 in 26-O-acyl isoAbeta1-42 (26-AIAbeta42). From the results, (1) the click peptide did not exhibit the self-assembling nature under physiological conditions due to one single modified ester; (2) photoirradiation of the click peptide and subsequent O-N intramolecular acyl migration afforded the intact Abeta1-42 with a quick and one-way conversion reaction (so-called "click"), while the click peptide was stable under nonphotolytic or storage conditions. In addition, it is advantageous that no additional fibril inhibitory auxiliaries were released during conversion to Abeta1-42. This method provides a novel system useful for investigating the dynamic biological functions of Abeta1-42 in AD by inducible activation of Abeta1-42 self-assembly.

Inhibition of the formation of amyloid β‐protein fibrils using biocompatible nanogels as artificial chaperones

“…Native human Ab-(1-42) (15 lM) was incubated with nanogels in buffer at 37°C for 24 h and the aggregation was monitored by sizeexclusion chromatography (SEC) [25] and thioflavin T (ThT) assay [26,27], and transmission electron microscopy (TEM).…”

Total chemical synthesis of polypeptides and proteins: chemistry of ligation techniques and beyond

“…146 The protected acyl peptide was stable, even after incubating at 37 C in PBS. It was also stable up to 24 assembly and aggregation.…”

Chemical Strategies for Controlling Protein Folding and Elucidating the Molecular Mechanisms of Amyloid Formation and Toxicity

“…A key advantage of O-acyl or S-acyl isopeptide units over pseudoproline building blocks is that they are stable following standard peptide cleavage methods with TFA and can thus further facilitate purification and handling beyond the synthesis stage. Furthermore, many N(Y) protecting groups have been explored, and a variety of triggering systems such as pH, [22][23][24][25][26] enzymes, 27 reducing agents, 28 and light 29,30 have been developed for restoring the native peptide backbone, some of which are even compatible with in vivo studies (vide infra).…”

“…One advantageous feature of switch peptides based on X → N acyl migration is their rapid response: Y protecting group removal rapidly establishes the native peptide bond and the desired conformational transition within seconds to minutes. 22,29,30 Another distinct advantage of these systems is the diverse choice of triggering methodologies that have been developed for inducing Y protecting group cleavage and conformational switching, including pH, 22,23,25 enzymatic cleavage, 27 reducing agents, 28 and light 29,30 (Fig. 3).…”