title: Development of O-acyl isopeptide method.
abstract: During over a decade of study on aspartic protease inhibitors and water-soluble prodrugs, in 2003, we discovered that the presence of an O-acyl instead of N-acyl residue within the peptide backbone significantly changed the secondary structure of the native peptide. In addition, the target peptide was subsequently generated by an O-N intramolecular acyl migration reaction. These findings led to the development of a novel method, called "O-acyl isopeptide method," for the synthesis of peptides containing difficult sequence. Further application of the method to Alzheimer's Abeta1-42 revealed that the O-acyl isopeptide of Abeta1-42 could be effectively synthesized and stored without spontaneous self-assembly. Intact monomer Abeta1-42 could then be obtained from the isopeptide under physiological experimental conditions. We named the O-acyl isopeptide as "Click Peptide," because of its "quick and easy one-way conversion" to the parent Abeta1- 42. Application of the click peptide has provided a new basis for the investigation of the biological functions of Abeta1-42 by inducible activation of its self-assembly. The O-acyl isopeptide method has further evolved as a general method for peptides synthesis with our recent developments of "O-acyl isodipeptide units" and "racemization-free segment condensation methodology." Isodipeptide units have enabled routine use of the O-acyl isopeptide method by avoiding the often difficult esterification reaction on resin. "Racemizationfree segment condensation methodology" has been achieved by employing N-segments possessing a C-terminal urethaneprotected O-acyl Ser/Thr residues. The synthesis of long peptides/proteins by racemization-free segment condensation has thus become possible at Ser/Thr residues instead of Cterminal Gly/Pro residues. As the O-acyl isopeptide method becomes more widely utilized, we have composed this review to facilitate its application for the production of peptides and proteins.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, 21st Century COE Program, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Youhei
authors.initials: Y
authors.lastname: Sohma
authors.forename: Taku
authors.initials: T
authors.lastname: Yoshiya
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Taniguchi
authors.forename: Tooru
authors.initials: T
authors.lastname: Kimura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D000215:Acylation; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry; D008722:Methods; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42)