Poly(ADP-ribosylation): Beneficial effects of its inhibition.

Poly(ADP-ribosylation) is a post-translational modification of proteins playing a crucial role in basic cellular processes, including DNA repair and replication, transcription and cell death. The biochemical reaction of poly(ADP-ribosylation) consists of the conversion of ß-NAD+ into ADP-ribose, and the further formation of polymers of variable length and structure bound to nuclear protein acceptors. Polymer synthesis and degradation are performed respectively by poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) enzymes. Although poly(ADP-ribosylation) is considered as an emergency reaction towards DNA damage, high levels of PARP activation cause NAD depletion and consequent necrosis, thus having a pathogenetic role in many diseases. As for chemical compounds able to inhibit poly(ADP-ribosylation), since the discovery of benzamide and nicotinamide, potent derivatives have been developed and new molecules have been tested. Pharmacological inhibition of PARP enzymes proved to reverse the noxious effects of ROS, thus exerting a protection towards a number of pathological conditions. Moreover, the combined treatment of tumors with PARP inhibitors and anticancer agents has been shown to have a beneficial effect in cancer therapy. Remarkably, pharmacological inactivation of poly(ADP-ribosylation) represents a novel therapeutical strategy to limit cellular injury and to improve the outcome of a variety of diseases. For these reasons, at present a lot of Companies and research laboratories are actively involved in the modeling of new compounds able to modulate poly(ADP-ribosylation).