NEW CHEMICALSENTITIES AND UNIQUE TARGEST FOR HCMV
The overall goal of the proposed research is to design, synthesize and evaluate new heterocyclic compounds, I nucleoside analogs, and prodrugs thereof as potential drugs for the treatment of herpesvirus infections, particularly those caused by human cytomegalovirus (HCMV). Compound design will be based upon our recent I discoveries of new lead compounds and on evidence for new antiviral targets. The latter studies will be based upon preliminary data which show a unique mode of action for new compounds. The overall approach will involve interactions among two synthesis projects, in vitro biological evaluation, virological and biochemical studies, and in vivo evaluation plus initial toxicology and pharmacokinetics. The primary rationale is to design and synthesize compounds that will be potent and specific inhibitors of HCMV replication. The detailed specific aims by which these objectives will be accomplished are described in the specific aims sections for each of the research projects. The aims can be summarized as follows: 1) Research Projects 1 and 2 will design and synthesize new compounds and prodrugs as potential agents for HCMV infections. The synthetic efforts will be guided by feedback from the biological components of the Program. 2) Research Project 3 will provide initial evaluation of new compounds for activity against HCMV (plaque reduction and yield reduction) and herpes simplex virus type 1 (HSV-1) as well as for cytotoxicity in uninfected cells. This I project also will be responsible for investigating the mode of action of new and existing compounds to better I understand their action and also to identify new viral drug targets. Studies will include in vitro drug metabolism, I inhibition of certain target enzymes or biological processes, molecular biology, and viral genetics. 4) The Scientific Core will provide more extensive in vitro evaluation of new compounds against other human herpes viruses and animal herpesviruses, in vivo testing of the most promising new compounds, plus initial toxicology and pharmacokinetic evaluation. In these ways, we shall provide a comprehensive program for the critical initial phases of drug discovery and development of new therapies for an important AIDS-associated opportunistic infection.
ANTIVIRAL STUDIES ON IMPROVED PRODRUGS FOR BIODEFENSE
This research proposal is subcontract portion of a study to be joint with other investigators, principally Kyung Dall Lee, Ph.D., University of Michigan and Charles McKenna, Ph.D., University of Southern California. The principal investigator is John Hilfinger, Ph.D. at Therapeutic Systems Research Laboratories, Inc., Ann Arbor, MI. The overall objective of the research project (of which the School of Dentistry, University of Michigan subcontract is a part) is to apply prodrug strategy for the improvement of antiviral, drugs used to treat viral infections of concern in biodefense. While recent research in this area has provided a modest increase in the number of drug candidates for treatment of these diseases, many potential antiviral agents are precluded from clinical use due to their extremely low oral bioavailability. Strategies that can improve the oral bioavailability of approved drugs as well as potent new drug candidates will facilitate the development of highly effective antiviral agents and reduce undesirable properties such as drug toxicity, poor patient compliance, and high costs associated with current therapy.
The specific aims of this portion of this project are to evaluate the antiviral activity and cytotoxicity of new compounds and new prodrugs synthesized in our collaborators laboratories. Evaluation will be for activity against viruses in each of the National Institute of Allergy and Infectious Diseases (NIAID) priority pathogens categories A, 8, and C. In Category A we shall study the effects of compounds on the replication of two DNA viruses, cow pox and vaccinia viruses -which are surrogates for smallpox virus, and an RNA virus, dengue virus. In Category 8 we shall study a RNA virus, Venezuelan equine encephalitis virus, and in category C we will study yellow fever virus. In addition to assessing the activity of new compounds and prodrugs against these viruses, we shall determine their cytotoxicity in at least two human cell lines. We also shall initiate preliminary mode of action studies on any new compounds with promising antiviral activity and low cytotoxicity.
Together these studies will greatly expand knowledge about the use of new compounds and unique prod rugs as biodefense agents and should identify compounds for additional preclinical and clinical evaluation.