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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 damage sensor and signalling molecule. 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. This 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. Activation of PARP 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. Moreover, PARP inhibitors may have additional, potential utility as anticancer agents, radiosensitizers and antiviral agents. In the present article we overview the structures and pharmacological actions of various pharmacological classes of compounds which inhibit the catalytic activity of PARP.
Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.