Although cell-based screening has been used successfully throughout the drug-discovery field, it is problematic when screening for antiviral compounds. This is because it requires inoculation of infectious virus onto the cells and the production of additional infectious progeny virus. Handling such infectious material is not easily compatible with the high throughput process of screening large libraries of compounds. Partial viral replication systems offer a way around this problem. Viral genomes which lack one or more genetic elements that are essential for carrying out a complete replication cycle offer a system in which viral genomic replication and many other viral pathways occur within cells, but no infectious virus is produced. A screening process that utilizes these incomplete viral genomes can identify inhibitors of any biochemical pathway involved in viral genome replication. In this proposal we plan to expand the capabilities of this approach to be able to screen for multiple viruses simultaneously. By combining cell lines, each of which contain a partially replicating viral genome, we can screen for antiviral activity against each of the viruses simultaneously. In addition to measuring the effect of a compound on genomic replication of several viruses, this system provides information on the specificity of the antiviral effect. This information is helpful in accessing whether the effect is acting on a specific viral target or on a cellular target and thus exerting its effect on the virus(es) indirectly. In addition this approach allows for the identification of compounds which exhibit broad antiviral activity and could therefore be effective against more than one virus.
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