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Synthesis of an O ‐acyl isopeptide by using native chemical ligation in an aqueous solvent system
Author(s) -
Kawashima Hiroyuki,
Kuruma Tomomi,
Yamashita Masayuki,
Sohma Youhei,
Akaji Kenichi
Publication year - 2014
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.2622
Subject(s) - native chemical ligation , chemistry , aqueous solution , combinatorial chemistry , solvent , ligation , biochemistry , organic chemistry , chemical synthesis , biology , in vitro , microbiology and biotechnology
O ‐Acyl isopeptides, in which the N ‐acyl linkage on the hydroxyamino acid residue (e.g. Ser and Thr) is replaced by an O ‐acyl linkage, generally suppress unfavorable aggregation properties derived from the corresponding parent peptides. Here, we report the synthesis of an O ‐acyl isopeptide of 34‐mer pyroGlu‐ADan (2), a component of amyloid deposits in hereditary familial Danish dementia, by using native chemical ligation. Native chemical ligation of pyroGlu 1 ‐ADan(1‐21)‐SCH 2 CH 2 SO 3 − Na + (3) and Cys 22 ‐ O ‐acyl isopeptide (4), in which the amino group of the Ser 29 residue at the isopeptide moiety was protected by an allyloxycarbonyl group, proceeded well in an aqueous solvent to yield a ligated O ‐acyl isopeptide (5). Subsequent disulfide bond formation and deprotection of the allyloxycarbonyl group followed by HPLC purification gave 2 with a reasonable overall yield. 2 was converted to the parent peptide 1 via an O‐to‐N acyl migration reaction. The sequential method, namely (i) native chemical ligation of the O ‐acyl isopeptide, (ii) HPLC purification as the O ‐acyl isopeptide form, and (iii) O‐to‐N acyl migration into the desired polypeptide, would be helpful to solve problems with HPLC purification of hydrophobic polypeptides in the process of chemical protein synthesis. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.