The ultimate goal of this project is the discovery of therapeutic compounds for the treatment of human cytomegalovirus (HCMV) infections. HCMV is the most common congenital infection in humans with about 40,000 infected children born each year in the U.S. It is estimated that 10-15 percent of these infants exhibit long-term neurological pathology making HCMV the leading infectious cause of central nervous system maldevelopment in newborn children. HCMV disease is also a common posttransplantation complication in solid organ allograft recipients with more than 60 percent of heart, kidney and liver allograft recipients developing active HCMV infections. A new system for drug discovery, called Combinatorial Recognition, will be used to identify compounds that block HCMV replication. This innovative technology for drug discovery can be focused upon any relevant gene product regardless of the protein's biochemical function. While the immediate therapeutic target in this proposal is the HCMV DNA polymerase accessory factor, the technology can be applied to other essential HCMV genes as well as essential genes of other human pathogens. Initially active site probes for the UL44 gene will be identified. Subsequently these probes will be utilized in high throughput screens of combinatorial chemical compounds libraries. Active compounds will be further evaluated in biochemical and anti-viral tests. PROPOSED COMMERCIAL APPLICATION This work is directed towards the identifications of therapeutic compounds for the treatment of cytomegalovirus infections in humans. Improvements to the technology being utilized will be of commercial value for the identification of compounds to treat other viral and infectious diseases.
Thesaurus Terms:antiviral agent, biotechnology, chemical registry /resource, cytomegalovirus, drug screening /evaluation DNA replication origin, chimeric protein, glutathione transferase, peptide library, protein sequence Sf9 cell line, affinity chromatography, molecular cloning, nucleic acid sequence, transfection vectorNational Institute of Allergy and Infectious Diseases (NIAID)
