# Convergent Approach Toward ADP‐Ribosylated Peptides via a Chemoselective Phosphate Condensation

## TL;DR

This paper introduces a new method to build ADP-ribosylated peptides by combining two chemical parts in a precise and efficient way.

## Contribution

A convergent, chemoselective method for assembling ADP-ribosylated peptides, including the first synthetic di-ADP-ribosylated peptide.

## Key findings

- A regio- and chemoselective condensation method was developed to form pyrophosphate bonds in ADP-ribosylated constructs.
- A di-ADP-ribosylated peptide was synthesized as the first example of a synthetic oligo-ADP-ribosylated peptide.
- A solid-phase approach enabled the preparation of a phosphoadenosyl-ADPr fragment for peptide conjugation.

## 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.

This research presents a convergent approach for synthesizing well‐defined ADP‐ribosylated peptides. It involves a regio‐ and chemoselective condensation of phosphoadenosyl (ADPr) fragments with phosphoribosyl peptides, allowing for the creation of various ADP‐ribosylated peptides, including a di‐ADP‐ribosylated‐peptide as the first example of a synthetic oligo‐ADP‐ribosylated peptide.