The objective of this core is to provide a resource for preclinical evaluation of new compounds synthesized at The University of Michigan and Wayne State University for antiviral activity against members of the herpesvirus group. Initially, the antiviral activity against Herpes Simplex virus types 1 and 2 (HSV-1, HSV-2) and cytomegalovirus (CMV) will be confirmed and also tested against murine CMV (MCMV), Varicella-Zoster virus (VZV), Epstein-Barr virus (EBV), Human Herpesvirus Type 6 (HHV-6), and Human Herpesvirus Type 8 (HHV-8). Efficacy, cell cytotoxicity, and anti- proliferative activity will be assessed in cultures of human and mouse cells. Compounds that have good in vitro activity and low toxicity against HSV-l, HSV-2, or MCMV will then be tested in experimental animal infections which are established models of severe human herpesvirus infections. The animal models to be utilized include: l) intraperitoneal inoculation of normal mice with MCMV, a model for acute and chronic disseminated disease; 2) intraperitoneal inoculation of severe combined immunodeficient (SCID) mice with MCMV, a model for acute disseminated CMV disease in the immunocompromised host; 3) SClD mice implanted with human fetal tissue which will then be infected with HCMV; 4) intraperitoneal inoculation of weanling mice with HSV-l, a model for herpes encephalitis; and 5) intraperitoneal inoculation of weanling mice with HSV-2, a model for neonatal herpes. 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% so that a maximum level of sensitivity in determining antiviral activity can be obtained; 4) evaluate several concentrations of drug initiated at various times after viral challenge; and 5) determine the effect of antiviral therapy on mortality, mean day of death, and viral replication in major target organs. For promising lead compounds, pharmacokinetics, oral bioavailability, and toxicity to the major organ systems will be performed in mice.
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