Click peptides -: Chemical biology-oriented synthesis of Alzheimer's disease-related amyloid β peptide (Aβ) analogues based on the "O-acyl isopeptide method"

A clear understanding of the pathological mechanism of amyloid beta peptide (A beta) 1-42 a currently unexplained process, would be of great significance for the discovery of novel drug targets for Alzheimer's disease (AD) therapy. To date, though, the elucidation of these A beta 1-42 dynamic events has been a difficult issue because of uncontrolled polymerization, which also poses a significant obstacle in establishing experimental systems with which to clarify the pathological function of A beta 1-42. We hove recently developed chemical biology-oriented pH- or phototriggered "click peptide" isoform precursors of A beta 1-42, based on the "O-ocyl isopeptide method", in which a native amide bond at a hydroxy-amino acid residue, such as Ser, is isomerized to an ester bond, the target peptide subsequently being generated by an O-N intramolecular acyl migration reaction. These click peptide precursors did not exhibit any self-assembling character under physiological conditions, thanks to the presence of the one single ester bond, and were able to undergo migration to give the target A beta 1-42 in a quick and easy, one-way (so-called "click")conversion reaction. The use of click peptides could be a useful strategy to investigate the biological functions of A beta 1-42 in AD through inducible activation of A beta 1-42 self-assembly.