PARP and PARG as novel therapeutic targets

Poly(ADP-ribose) is synthesized by poly(ADP-ribose) polymerase (PARP) from β-nicotinamide adenine dinucleotide (NAD⁺). 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. PARP₁, 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 PARP₁/PARG cycle results in depletion of NAD⁺ and ATP, which can be prevented by inhibiting PARP₁ 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.