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Abstract
Grant Number: 1R43AI051765-01A1 PI Name: BELCOURT, MICHAEL F. PI Email: mbelcourt@vionpharm.com PI Title: Project Title: Determination of Triapine Antiviral Activity Abstract: DESCRIPTION (provided by applicant): 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.
Thesaurus Terms:
antiviral agent, combination chemotherapy, enzyme inhibitor, microorganism disease chemotherapy, pyridine, ribonucleotide reductase
cytotoxicity, deoxyribonucleoside triphosphate, drug screening /evaluation, hepatitis B, herpes simplex virus 1, human immunodeficiency virus 1, mitochondria, nucleoside analog, pharmacokinetics, phosphorylation, virus replication
autoradiography, cell line, microorganism culture
Institution: VION PHARMACEUTICALS, INC. 4 SCIENCE PK NEW HAVEN, CT 06511 Fiscal Year: 2003 Department: Project Start: 15-SEP-2003 Project End: 14-MAR-2004 ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES IRG: ZRG1