Convergent approach toward ADP‐ribosylated peptides via a chemoselective phosphate condensation

Abstract

The preparation of well-defined ADP-ribosylated peptides is essential for studying the functional implications of this post-translational modification. While methodologies exist for the chemical synthesis of short oligo-ADPr fragments and mono-ADP-ribosylated peptides separately, combining the two distinct chemistries, required to assemble them, has remained challenging. In this research, we employ a methodology for the regio- and chemoselective condensation of two phosphomonoesters to convergently install the pyrophosphate bond in ADP-ribosylated constructs. A diverse set of phosphoribosylated peptides, varying in the amino acid acceptor, was prepared and condensed with adenosine monophosphate to yield mono-ADP-ribosylated peptides. Furthermore, a solid-phase approach was developed to access a phosphoadenosyl-ADPr fragment, which was used to prepare a di-ADPr-peptide as the first example of a synthetic oligo-ADP-ribosylated peptide. Overall, the work presented here extends synthetic methodology for the preparation of well-defined ADP-ribosylated peptides.