Recent advances in the synthesis of poly (ADP-ribose)

Abstract

Poly (ADP-ribose) (PAR), a dynamic and reversible post-translational modification, is a structurally complex biopolymer synthesized via ADP-ribosylation, utilizing NAD⁺ as a substrate and catalyzed by ADP-ribosyltransferases (ARTs). PAR exists as linear or branched chains of up to 200 ADP-ribose units, playing pivotal roles in DNA repair, chromatin remodeling, transcriptional regulation, and cell death. The structural intricacy of PAR—marked by labile pyrophosphate linkages, stereochemical diversity, and branching architectures—poses significant synthetic challenges, necessitating innovative strategies integrating carbohydrate chemistry, enzymatic engineering, and phosphate coupling. Recent advances over the past decade have enabled the chemical and chemoenzymatic synthesis of well-defined PAR fragments, oligomers, and probes, facilitating breakthroughs in structural biology, interactome mapping, and therapeutic discovery. This review highlights key methodologies, including phosphoramidite-based assembly, development of photoaffinity probes and chemoenzymatic elongation with engineered ARTs, which collectively advance our understanding of PAR’s biological functions and therapeutic potential.