Chemical O-ADP-Ribosylations: Synthesis and Bioconjugation of ADPr-Peptides/Proteins from NAD+

Abstract

ADP-ribosylation is a complex post-translational modification involved in key physiological processes and associated with various health and disease states. The growing interest in ADP-ribosylation necessitates straightforward and efficient synthetic methods for the preparation of ADP-ribosylated peptides/proteins. In this study, we report a facile reaction between nicotinamide adenine dinucleotide (NAD+) and alcohols promoted by a combination of ionic liquids, yielding up to 94% with α:β ratios ranging from 88:12 to 99:1 and a switchable configuration selectivity. This method significantly simplifies the production of ADP-ribosylated peptides and proteins, enabling diverse applications. It allows detailed investigation of side-chain structure-activity relationships, facilitates two-step clickable conjugation of ADP-ribosyl groups to proteins, and, for the first time, enables non-enzymatic synthesis of well-defined ADP-ribosylated peptides/proteins from natural counterparts and NAD+.