Poly(ADP-ribose)polymerase Inhibition - Where Now?

Abstract

The poly(ADP-ribose)polymerases (PARPs) catalyse the transfer of ADP-ribose units from the substrate NAD(+) to acceptor proteins, biosynthesising polyanionic poly(ADP-ribose) polymers. A major isoform, PARP-1, has been the target for design of inhibitors for over twenty-five years. Inhibitors of the activity of PARP-1 have been claimed to have applications in the treatment of many disease states, including cancer, haemorrhagic shock, cardiac infarct, stroke, diabetes, inflammation and retroviral infection, but only recently have PARP-1 inhibitors entered clinical trial. Most PARP-1 inhibitors mimic the nicotinamide of NAD(+) and the structure-activity relationships are understood in terms of the structure of the catalytic site. However, five questions remain if PARP-1 inhibitors are to realise their potential in treating human diseases. Firstly, the consensus pharmacophore is a benzamide with N-H conformationally constrained anti to the carbonyl-arene bond but this is also a "pharmacophore" for insolubility in water; can water-solubility be designed into inhibitors without loss of potency? Secondly, some potential clinical applications require tissue-selective PARP-1 inhibition; is this possible through pro-drug approaches? Thirdly, different diseases may require therapeutic PARP-1 inhibition to be either short-term or chronic; are there potential problems associated with chronic inhibition of this DNA-repair process? Fourthly, PARP-1 is one of at least eighteen isoforms; is isoform-selectivity essential, desirable or even possible? Fifthly, PARP activity can be inhibited in cells by inhibition of poly(ADP-ribose)-glycohydrolase (PARG); will this be a viable strategy for future drug design? The answers to these questions will determine the future of disease therapy through inhibition of PARP.

Resveratrol prevents streptozotocin-induced diabetes by inhibiting the apoptosis of pancreatic β-cell and the cleavage of poly (ADP-ribose) polymerase

“…When the amount of NAD + is exhausted, pancreatic β-cells are destroyed by apoptosis. NA provides sufficient NADH and acts as a weak PARP inhibitor, and is known to inhibit STZ-induced diabetes [15]. In our study, RSV inhibited the cleavage of PARP but did not reduce the expression of full-length PARP, indicating that RSV inhibits PARP cleavage.…”

A Key Role for Poly(ADP-Ribose) Polymerase-1 Activity during Human Dendritic Cell Maturation

“…The present findings, along with evidence that suppression of PAR formation also affects immunocompetence of T and B lymphocytes (6,13,14), help to explain why inhibitors of PARP-1 exert widespread immunosuppression (65). Finally, although the effects of PARP-1 inhibitors on DCs in vivo remains to be evaluated, we infer that these compounds, currently tested in different clinical trials in humans (66), can be harnessed to develop innovative therapies aimed at promoting graft survival or combating autoimmune disorders.…”

Mechanisms of Chemoresistance to Alkylating Agents in Malignant Glioma

“…Potential applications in the nonmalignant setting have recently been reviewed (56,57). In the realm of cancer therapy, preclinical models have shown that inhibition of PARP-1 can potentiate the activity of both radiotherapy and a variety of chemotherapeutic agents (58 -64), and PARP-1 inhibitors have also shown single-agent activity against certain tumor cell lines (65,66).…”