Poly(ADP-ribose) polymerase-1 (PARP-1) is the principal member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosyl)ating enzymes. PARP-1 functions as a DNA nick sensor enzyme. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors and PARP itself. Poly(ADP-ribosyl)ation contributes to inflammatory signal transduction processes. In addition, oxidative stress-induced overactivation of PARP consumes NAD+ and consequently ATP, culminating in cell dysfunction or necrosis. PARP activation has been implicated in the pathogenesis of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis and various other forms of inflammation. Therefore, inhibition of PARP by pharmacological agents may prove useful for the therapy of these diseases, as has been shown in preclinical animal models of these diseases. Moreover, PARP inhibitors may have additional, potential utility as anticancer agents, radiosensitizers and antiviral agents. Here we overview the structures and pharmacological actions of various pharmacological classes of compounds which inhibit the catalytic activity of PARP and will present novel biochemical and pharmacological data, as well as in vivo efficacy data with PJ34, a potent, phenanthridinone-based PARP inhibitor, as well as with EB47 and INO-1001, members of two novel series of ultrapotent PARP inhibitors. References: 1.Virág L, Szabó C: The therapeutic potential of PARP inhibition. Pharmacological Reviews, 2002; 54: 375-429 2.Jagtap P, Soriano FG, Virag L et al: Novel phenanthridinone inhibitors of poly(ADP-ribose) synthetase: potent cytoprotective and anti-shock agents. Crit Care Med, 2002; 30: 1071-82 3.Southan GJ, Szabó C: Inhibitors of poly(ADP-ribose) polymerase. Current Med Chem, in press, 2003

Keywords: pharmacological inhibitors, NAD, competitive inhibition, potency, efficacy