Poly(ADP-ribose) polymerases (PARPs) are involved in the regulation of many cellular functions.
The chromatin-associated enzyme poly(ADP-ribose) polymerase uses NAD as substrate to catalyze both the covalent transfer of ADP-ribose to a variety of nuclear protein acceptors and subsequently the transfer of an additional 60 to 80 ADP-ribose units to the initial moiety.
Nuclear proteins that become predominantly poly(ADP-ribosyl)ated include nucleosomal core histones, histone H1 (MIM.142711), HMG proteins (HMGs), and topoisomerases I (MIM.126420) and II (MIM.126430).
ADP ribosyltransferase is required for cellular repair. Inhibitors of this enzyme potentiate the lethal effects of noxious agents.
During repair, NAD+ is consumed and the NAD+ content of the cell decreases. Concomitantly, nuclear proteins are ADP-ribosylated. The enzyme is induced by single-strand breaks in DNA which serve as cosubstrate for the reaction.
Therapeutics
Three consequences of the activation of PARP1, which is the main isoform of the PARP family, are particularly important for drug development: first, its role in DNA repair; second, its capacity to deplete cellular energetic pools, which culminates in cell dysfunction and necrosis; and third, its capacity to promote the transcription of pro-inflammatory genes.
Consequently, pharmacological inhibitors of PARP have the potential to enhance the cytotoxicity of certain DNA-damaging anticancer drugs, reduce parenchymal cell necrosis (for example, in stroke or myocardial infarction) and downregulate multiple simultaneous pathways of inflammation and tissue injury (for example, in circulatory shock, colitis or diabetic complications).
The first ultrapotent novel PARP inhibitors have now entered human clinical trials. This article presents an overview of the principal pathophysiological pathways and mechanisms that are governed by PARP, followed by the main structures and therapeutic actions of various classes of novel PARP inhibitors.
References
Haince JF, Rouleau M, Hendzel MJ, Masson JY, Poirier GG. Targeting poly(ADP-ribosyl)ation: a promising approach in cancer therapy. Trends Mol Med. 2005 Oct;11(10):456-63. PMID: 16154385
Jagtap P, Szabo C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov. 2005 May;4(5):421-40. PMID: 15864271
