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

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.