Discovery of PARP1-Sparing Inhibitors for Protein ADP-Ribosylation.

Poly-ADP-ribose polymerases (PARPs) that catalyze cellular ADP-ribosylation play important roles in human health. PARP inhibitors have found success in the clinic for cancer treatment. However, isoform-specific inhibitors are needed for improved safety.

A ribose-functionalized NAD with versatile activity for ADP-ribosylation.

An NAD featuring an adenosyl 4'-azido functions as a general substrate for poly-ADP-ribose polymerases. Its derived mono- and poly-ADP-ribosylated proteins can be adequately recognized by distinct ADP-ribosylation-specific readers. This molecule represents the first ribose-functionalized NAD with versatile activities across different ADP-ribosyltransferases and provides insight into developing new probes for ADP-ribosylation.