Investigation of the Antiviral Activity of PNU-183792, a 4-Oxo-Dihydroquinoline, Against Human Herpes Simplex Virus 1
Ricketts, Robert M.
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Human herpes simplex virus 1 (HSV-1), which can cause oral and genital blister like vesicles, is prevalent in the United States. The HSV-1 virion consists of an icosahedral capsid, tegument, and an envelope containing viral glycoprotein spikes on its surface (Roizman et al., 1993). PNU-183792, a 4-oxo-dihydroquinoline non-nucleoside inhibitor, is a broad-spectrum antiviral compound that has proven effective against many human and animal herpes viruses including HSV-1 (Brideau et al., 2002). Repeated exposure ofHSV-1 to the presence of PNU-183792 resulted in the isolation of a resistant virus (Thomsen et al., 2002). The phenotype of the resistant mutant virus was mapped to an amino acid change within conserved domain III of the HSV-1 DNA polymerase at position 823 (Valine -> Alanine) (Thomsen et al., 2002). Following a series of restriction digests and PCR, position 823 was mutated to every possible amino acid. Replication rates were found for all mutant viruses and compared to that of wild type. Virus growth was then tested in the presence of PNU-183792. PNU-183792 is a potent antiviral compound that offers the possibility for development of a wide-ranging herpes compound with a new mechanism of action (Thomsen et al., 2002). Testing exactly what amino acid changes at position 823 of the viral DNA polymerase confers resistance to PNU-183792 should offer some insight into the compounds mechanism of action.