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 Aβ1‐42 revealed that the O‐acyl isopeptide of Aβ1‐42 could be effectively synthesized and stored without spontaneous self‐assembly. Intact monomer Aβ1‐42 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 Aβ1‐ 42. Application of the click peptide has provided a new basis for the investigation of the biological functions of Aβ1‐42 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. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 88: 253–262, 2007.
This article was originally published online as an accepted preprint. The ‘Published Online’ date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at [email protected]