# Solid‐Phase Synthesis and Biological Evaluation of Peptides ADP‐Ribosylated at Histidine

## TL;DR

Scientists developed a method to synthesize peptides with ADP-ribose attached to histidine and found they are stable and resistant to degradation.

## Contribution

A new synthetic strategy for creating histidine-containing peptides ADP-ribosylated at specific sites is introduced.

## Key findings

- A fully synthetic route to α-configured N(τ)- and N(π)-ADP-ribosylated histidine peptides was developed.
- The synthesized peptides are stable under various chemical conditions.
- The peptides are resistant to degradation by known ADP-ribosylhydrolases.

## Abstract

The transfer of an adenosine diphosphate (ADP) ribose moiety to a nucleophilic side chain by consumption of nicotinamide adenine dinucleotide is referred to as ADP‐ribosylation, which allows for the spatiotemporal regulation of vital processes such as apoptosis and DNA repair. Recent mass‐spectrometry based analyses of the “ADP‐ribosylome” have identified histidine as ADP‐ribose acceptor site. In order to study this modification, a fully synthetic strategy towards α‐configured N(τ)‐ and N(π)‐ADP‐ribosylated histidine‐containing peptides has been developed. Ribofuranosylated histidine building blocks were obtained via Mukaiyama‐type glycosylation and the building blocks were integrated into an ADP‐ribosylome derived peptide sequence using fluorenylmethyloxycarbonyl (Fmoc)‐based solid‐phase peptide synthesis. On‐resin installation of the ADP moiety was achieved using phosphoramidite chemistry, and global deprotection provided the desired ADP‐ribosylated oligopeptides. The stability under various chemical conditions and resistance against (ADP‐ribosyl) hydrolase‐mediated degradation has been investigated to reveal that the constructs are stable under various chemical conditions and non‐degradable by any of the known ADP‐ribosylhydrolases.