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

A clear understanding of the dynamic events of amyloid β peptide (Aβ) 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 Aβ1−42 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 Aβ1−42. On the basis of the O-acyl isopeptide method, we herein developed a novel photo-triggered “click peptide” of Aβ1−42, for example, 26-N-Nvoc-26-AIAβ42, in which the photocleavable 6-nitroveratryloxycarbonyl (Nvoc) group was introduced at the α-amino group of Ser²⁶ in 26-O-acyl isoAβ1−42 (26-AIAβ42). 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 Aβ1−42 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 Aβ1−42. This method provides a novel system useful for investigating the dynamic biological functions of Aβ1−42 in AD by inducible activation of Aβ1−42 self-assembly.