POLY(ADP-RIBOSE) POLYMERASE, A POTENTIAL TARGET FOR DRUGS - CELLULAR REGULATORY ROLE OF THE POLYMER AND THE POLYMERASE PROTEIN-MEDIATED BY CATALYTIC AND MACROMOLECULAR COLLIGATIVE ACTIONS (REVIEW)

The cellular coenzymatic role of NAD, being a pleiotropic cofactor for diverse cellular reactions, is extended to poly(ADP-ribose) and to th e highly abundant nuclear protein, poly(ADP-ribose) polymerase, with s pecial focus on the pharmacological action of ligands on the latter. T he polymer is defined to possess a helical configuration. From direct analyses of the polymer under physiological conditions, it is conclude d that the polymerase is dormant in normal tissues, but is activated u nder certain pathological conditions: malignancy, retroviral integrate containing cells, and in a variety of inflammatory states. The intera ction of poly(ADP-ribose) polymerase ligands with the DNA component of the active poly (ADP-ribose) polymerase - DNA complex is shown. A maj or cellular function of the poly(ADP-ribose) polymerase protein is its binding capacity to a large number of nuclear proteins and DNA sites, an effect which is induced by drugs that inhibit the polymerase activ ity. The malignancy-reverting effect of poly(ADP-ribose) polymerase li gand drugs is illustrated in chemically and oncovirally transformed ca ncer cells. The poly(ADP-ribose) polymerase ligand-induced cessation o f HIV replication is analyzed. Peroxynitrite-induced DNA damage-initia ted pathological responses are shown to be inhibited by a specific pol y(ADP-ribose) polymerase ligand. The irreversibly acting C-NO drugs ox idize asymmetric zinc fingers [poly (ADP-ribose) polymerase, HIV gag-p recursor protein] and act as anticancer and anti-HIV agents, an effect that is regulated by cellular concentration of GSH.