Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone is a novel ribonucleotide reductase inhibitor with antineoplastic activity that is 1000 times more potent than hydroxyurea as an inhibitor of ribonucleotide reductase with activity against cell lines resistant to hydroxyurea and gemcitabine. Hydroxyurea, widely used in the treatment of human malignancies, potentiates the antiviral activities of various nucleoside analogues against human immunodeficiency virus (HIV-1) and herpes simplex virus-1 and -2 (HSV-1 and -2). The preclinical data suggests that Triapine is superior to hydroxyurea as a cancer chemotherapeutic and thus warrants investigation as an adjuvant to antiviral therapies. This application proposes to investigate the potential of Triapine as an adjuvant to existing antiviral therapies by a) determining the levels of the dNTP pools in host cell lines following exposure to concentrations of Triapine, in combination with nucleoside analogues, yielding antiviral activity; b) measuring the effect of Triapine on nucleoside kinase enzymes to assess their impact on the recovery of specific dNTP pools and on the degree of phosphorylation of the nucleoside analogues; and c) assessing the toxicity and antiviral activity of Triapine combined with various nucleoside analogues (selected based on the impact of Triapine on specific dNTP pools) against HIV-1, HSV-1 and -2, and Hepatitis B virus.
