Thioester Ligation with AAHO Peptides

We report herein a new chemoselective ligation reaction between a peptide thioester and an aminoacyl-N-hydroxy peptide (AAHO peptide). In this ligation scheme, the thioester engages the nucleophilic N-hydroxyl group of the AAHO peptide in a thio-to-oxo transesterification reaction to form a transient O-acyl intermediate that rapidly rearranges to form a native peptide bond at the ligation junction. The N-hydroxyl auxiliary on the peptide bond next to the junction can be easily removed through the reductive cleavage of the N–O bond. Ubiquitination was demonstrated on a synthetic peptide containing Lys(Nε-glycyl-Nε-OH), an AAHO-modified lysine residue.