PARP and PARG as novel therapeutic targets

Poly(ADP-ribose) is synthesized by poly(ADP-ribose) polymerase (PARP) from beta-nicotinamide adenine dinucleotide (NAD(t)). It is mainly degraded by poly(ADP-ribose) glycohydrolase (PARG). The expanding family of PARP currently consists of PARP(1-3), vPARP, Tankyrase(1-2), and more members are being characterized. Similarly, the PARG family awaits more homologs to be identified. PARP(1), which is activated by DNA damage, accounts for >95% poly(ADP-ribose) synthesis. Poly(ADP-ribose) has a half-life of <1 min in vivo, due to its immediate degradation by PARG. The PARP(1)/PARG cycle results in depletion of NAD(t) and ATP, which can be prevented by inhibiting PARP, or PARG. After PARP1 was implicated in facilitating DNA repair, pharmaceutical companies began developing PARP inhibitors as potentiators to enhance chemotherapy and radiation therapy in cancers. Recent studies using PARP1 knockout mice and PARP inhibitors validated targeting the poly(ADP-ribose) pathway for ameliorating ischemia injury and abating inflammation. Multiple families of PARP and PARG inhibitors have been identified. A number of these inhibitors have demonstrated efficacy in animal models of cerebral ischemia, traumatic brain injury, Parkinson's disease, myocardial ischemia, retinal ischemia, kidney ischemia, type 1 diabetes, septic shock, hemorrhagic shock, arthritis, inflammatory bowel disease, multiple sclerosis and potentiation of chemotherapy. The therapeutic utility of PARP inhibitors is expected to be studied soon in clinical trials.