Core - IN Vivo and IN Vitro Evaluation

Kern, Earl R.

Abstract

The objective of this project is to provide a resource for in vivo evaluation of antiviral agents in experimental animal infections which are models of severe human herpesvirus diseases. The investigation of a new antiviral compound provided by the University of Michigan NCDDG-OI will include: 1) determination of the in vitro activity of the drug against appropriate representative viruses in both mouse and human tissue culture cells, 2) establishment of the maximum tolerated dose for each new drug prior to beginning treatment studies, and 3) an evaluation of the efficacy of the compound in the treatment of appropriate experimental viral infections in animal models. To determine the potential of new antiviral compounds for use in treatment of herpesvirus infections of humans, the following animal model infections will be utilized: 1) intraperitoneal inoculation of normal mice with MCMV, a model for acute and chronic disseminated CMV disease in normal hosts; 2) Intraperitoneal inoculation of MuLV LP-BM-5-induced immunosuppressed mice (MAIDS) with MCMV, a model for acute disseminated CMV disease in the immunocompromised host; 3) intraperitoneal inoculation of weanling mice with HSV-1 or HSV-2, models for acute HSV infection. The animal model systems have been developed to: 1) simulate a human herpesvirus disease; 2) utilize a natural route of infection where possible; 3) achieve infection or mortality rates of 80-90% from the viral challenge, so that a maximum level of sensitivity in determining the activity of the drug may be obtained; 4) evaluate several doses of the drug (maximum tolerated dose to minimum effective dose) initiated at various times after viral challenge and administered 2-3 times daily throughout the course of the infection; 5) allow determination of the effect of antiviral therapy on mortality, mean day of death, and viral replication in major target organs and; 6) determine the potential of combination chemotherapy. Specific antiviral agents to be tested in each animal model will be chosen according to background data generated from tissue culture sensitivity testing and discussions with the other project leaders and NIAID Staff.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Research Program--Cooperative Agreements (U19)
• Project #: 5U19AI031718-06
• Application #: 5205488
• Support Year: 6
• Fiscal Year: 1996

Publications

Chen, Jiong J; Wei, Yuan; Williams, John D et al. (2005) Design, synthesis, and antiviral evaluation of some polyhalogenated indole C-nucleosides. Nucleosides Nucleotides Nucleic Acids 24:1417-37

Williams, John D; Drach, John C; Townsend, Leroy B (2005) Synthesis and antiviral activity of some 2-substituted 3-formyl- and 3-cyano-5,6-dichloroindole nucleosides. Nucleosides Nucleotides Nucleic Acids 24:1613-26

Migawa, Michael T; Drach, John C; Townsend, Leroy B (2005) Design, synthesis and antiviral activity of novel 4,5-disubstituted 7-(beta-D-ribofuranosyl)pyrrolo[2,3-d][1,2,3]triazines and the novel 3-amino-5-methyl-1-(beta-D-ribofuranosyl)- and 3-amino-5-methyl-1-(2-deoxy-beta-D-ribofuranosyl)-1,5-dihydro-1,4,5,6,7 J Med Chem 48:3840-51

Kern, Earl R; Hartline, Caroll B; Rybak, Rachel J et al. (2004) Activities of benzimidazole D- and L-ribonucleosides in animal models of cytomegalovirus infections. Antimicrob Agents Chemother 48:1749-55

Williams, John D; Chen, Jiong J; Drach, John C et al. (2004) Design, synthesis, and antiviral activity of certain 3-substituted 2,5,6-trichloroindole nucleosides. J Med Chem 47:5753-65

Chien, Tun-Cheng; Saluja, Sunita S; Drach, John C et al. (2004) Synthesis and antiviral evaluation of polyhalogenated imidazole nucleosides: dimensional analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole. J Med Chem 47:5743-52

Williams, John D; Ptak, Roger G; Drach, John C et al. (2004) Synthesis, antiviral activity, and mode of action of some 3-substituted 2,5,6-trichloroindole 2'- and 5'-deoxyribonucleosides. J Med Chem 47:5773-82

Komazin, Gloria; Townsend, Leroy B; Drach, John C (2004) Role of a mutation in human cytomegalovirus gene UL104 in resistance to benzimidazole ribonucleosides. J Virol 78:710-5

Evers, David L; Komazin, Gloria; Ptak, Roger G et al. (2004) Inhibition of human cytomegalovirus replication by benzimidazole nucleosides involves three distinct mechanisms. Antimicrob Agents Chemother 48:3918-27

Porcari, Anthony R; Townsend, Leroy B (2004) An improved total synthesis of triciribine: a tricyclic nucleoside with antineoplastic and antiviral properties. Nucleosides Nucleotides Nucleic Acids 23:31-9