Amide-forming chemical ligation via O-acyl hydroxamic acids.

ABSTRACT: The facile rearrangement of "S-acyl isopeptides" to native peptide bonds via S,N-acyl shift is central to the success of native chemical ligation, the widely used approach for protein total synthesis. Proximity-driven amide bond formation via acyl transfer reactions in other contexts has proven generally less effective. Here, we show that under neutral aqueous conditions, "O-acyl isopeptides" derived from hydroxy-asparagine [aspartic acid-?-hydroxamic acid; Asp(?-HA)] rearrange to form native peptide bonds via an O,N-acyl shift. This process constitutes a rare example of an O,N-acyl shift that proceeds rapidly across a medium-size ring (t1/2 ? 15 min), and takes place in water with minimal interference from hydrolysis. In contrast to serine/threonine or tyrosine, which form O-acyl isopeptides only by the use of highly activated acyl donors and appropriate protecting groups in organic solvent, Asp(?-HA) is sufficiently reactive to form O-acyl isopeptides by treatment with an unprotected peptide-?thioester, at low mM concentration, in water. These findings were applied to an acyl transfer-based chemical ligation strategy, in which an unprotected N-terminal Asp(?-HA)-peptide and peptide-?thioester react under aqueous conditions to give a ligation product ultimately linked by a native peptide bond.

SUBMITTER: Dunkelmann DL 

PROVIDER: S-EPMC5899448 | biostudies-other | 2018 Apr

REPOSITORIES: biostudies-other