Semisynthesis of Peptoid–Protein Hybrids by Chemical Ligation at Serine

Chemical ligation protocols were explored for generating semisynthetic peptoid-protein hybrid architectures containing a native serine residue at the ligation site. Peptoid oligomers bearing C-terminal salicylaldehyde esters were synthesized and ligated to the N-terminus of the RNase S protein or the therapeutic hormone PTH(1-34) polypeptide. This technique will expand the repertoire of strategies to enable design of hybrid macromolecules with novel structures and functions not accessible to fully biosynthesized proteins.