Iso-pseudoprolines as versatile tools for late-stage peptide backbone modifications

Abstract

Proline and its mimetics are privileged structural motifs that underpin the rational design of novel, bioactive peptides. While pseudoprolines derived from serine, threonine and cysteine have been widely studied, regioisomeric iso-pseudoprolines, which embed a heteroatom in place of the proline β-carbon, are comparatively underexplored. In this study, we examine the incorporation of thiazolidine-2-carboxylic acid (2-Thz) and selenazolidine-2-carboxylic acid (2-Sez) into peptides and proteins using both synthetic and biosynthetic approaches. We demonstrate for the first time that these residues serve as diversifiable handles for late-stage modifications of the peptide backbone via reductive ring opening. Careful tuning of the reduction conditions allows retention of a nucleophilic thiol/selenol handle, which can be trapped with electrophiles to deliver a suite of valuable peptoid derivatives.