"Click peptides"--chemical biology-oriented synthesis of Alzheimer's disease-related amyloid beta peptide (abeta) analogues based on the "O-acyl isopeptide method".
A clear understanding of the pathological mechanism of amyloid beta peptide (Abeta) 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 Abeta1-42 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 Abeta1-42. We have recently developed chemical biology-oriented pH- or phototriggered "click peptide" isoform precursors of Abeta1-42, based on the "O-acyl isopeptide method", in which a native amide bond at a hydroxyamino 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 Abeta1-42 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 Abeta1-42 in AD through inducible activation of Abeta1-42 self-assembly.
Sohma
Youhei
Y
Department of Medicinal Chemistry Center for Frontier Research in Medicinal Science 21st Century COE Program, Kyoto Pharmaceutical University Yamashina-ku, Kyoto 607-8412, Japan.
Kiso
Yoshiaki
Y
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004952:Esters / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000138:chemical synthesis* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D000577:Amides; D016229:Amyloid beta-Peptides; D004952:Esters; D010446:Peptide Fragments; D020033:Protein Isoforms; C075222:amyloid beta-protein (1-42)