The treatment of herpes labialis the clinical manifestation of oral-facial infections by type 1 and to a limited extent type 2 herpes simplex viruses (HSV-1 and HSV-2), continues to be a major concern to health practitioners. Because of the localized cutaneous nature of the disease, topical drug administration is the ideal treatment route. Although a few antiviral drugs currently are available, they are not useful in the therapy of herpes labialis due to problems of topical drug bioavailability and/or systemic drug distribution. Recent developments in the molecular biology of herpesviruses have provided new strategies for aniviral chemotherapy. It is now know that herpes simplex virus codes for the important enzyme ribonucleoside diphosphate reductase and it seems clear that this enzyme can serve as a target for antiviral drugs. We have identified certain 2-acetylpyridine thiosemicarbazones which inhibit this enzyme and are potent and selective inhibitors of HSV-1 and HSV-2 replication. At the molecular level, these compounds inhibit cellular functions to a lesser extent than viral functions. In experimental animals, they are able to cross intact skin readily as evidenced by their efficacy in the cutaneous herpes guinea pig model. Consequently, there is excellent potential for the clinical application of these or related derivatives. The goals of this research proposal are to advance our knowledge of how these and newer derivatives act and to develop key compounds for the effective topical treatment of herpes labialis. These objectives will be accomplished through a series of subprojects which will (i) identify new derivatives and their metal chelates of 2-acetylpyridine thiosemicarbazone which selectively inhibit the viral ribonucleotide reductase, (ii) explore the potential to develop synergistic combinations of thiosemicarbazones and known antiviral drugs which act by inhibiting the viral DNA polymerase, (iii) select compounds which will not suppress immune function, (iv) select compounds which are efficacious and do not produce untoward side effects when applied to the skin of guinea pigs, and (v) trace the metabolic disposition of radiolabeled 2-acetylpyridine thiosemicarbazone and identify metabolites. Thus, the first two subprojects will study selected compounds or synergistic combinations of compounds to more clearly elucidate the mechanism by which the viral ribonucleotide reductase is inhibited while the last three subprojects will be used to advance both existing and newer compounds toward clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE008510-01
Application #
3222223
Study Section
(SRC)
Project Start
1987-09-01
Project End
1992-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Dentistry/Oral Hygn
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Prichard, M N; Shipman Jr, C (1995) Ribonucleotide reductase: an important enzyme in the replication of herpes simplex virus type 1 and a target for antiviral chemotherapy. Chemotherapy 41:384-95
Prichard, M N; Prichard, L E; Shipman Jr, C (1993) Inhibitors of thymidylate synthase and dihydrofolate reductase potentiate the antiviral effect of acyclovir. Antiviral Res 20:249-59
Prichard, M N; Prichard, L E; Shipman Jr, C (1993) Strategic design and three-dimensional analysis of antiviral drug combinations. Antimicrob Agents Chemother 37:540-5
Prichard, M N; Prichard, L E; Baguley, W A et al. (1991) Three-dimensional analysis of the synergistic cytotoxicity of ganciclovir and zidovudine. Antimicrob Agents Chemother 35:1060-5
Prichard, M N; Shipman Jr, C (1990) A three-dimensional model to analyze drug-drug interactions. Antiviral Res 14:181-205
Turk, S R; Kik, N A; Birch, G M et al. (1989) Herpes simplex virus type 1 ribonucleotide reductase null mutants induce lesions in guinea pigs. Virology 173:733-5