The most common form of herpesvirus infection of the oral-facial complex results in herpes labialis. These are usually recurrent lesions which cause considerable pain and discomfort to a large segment of the population. In addition, a number of severe and often life threatening diseases are produced by human herpesvirus. These include herpetic keratitis (a major cause of blindess) and herpes encephalitis, both caused by herpes simplex type 1. Immunologic approaches have not been very successful in treating herpetic infections as they have been with such viral diseases as smallpox and polio. Recent interest has shifted to chemotherapy as a means of combating herpesvirus infections. Most of the anti-herpes agents in use today are directed at a few herpesvirus specific enzymes, whose inhibition elicits the drug's selective effect. However, most current chemotherapeutic agents appear to suffer from narrow therapeutic limits and development of resistant viral strains. One approach to try and circumvent these problems would be to identify other virally induced enzymes. In this way a broader base could be established from which rational approaches to drug design can be expanded. The principal investigator has recently observed two new enzyme funcitions that are induced in HSV type 1 and 2 infected cells. The enzymes are dUTP nucleotidohydrolase and uracil DNA glycosylase. The proposed work will entail: 1) Purification and characterization of these viral induced enzymes and comparing their characteristics to the host cell enzymes. This work is intended to further establish physical as well as kinetic differences between HSV derived enzymes and their host cell counterparts. 2) Isolation and in-vitro translation of HSV mRNA will be performed to discern if these are viral coded enzymes. 3) By testing analogs of the substrates and products of the dUTPase and glycosylase, information will be generated to help predict structures of future antiviral agents used in inhibiting, selectively the viral derived dUTPase and glycosylase. 4) Cell-free systems will be utilized to analyze activation by phosphorylation of possible inhibitors of dUTPase. 5) Analysis will be made as to whether glycosylase inhibitors are mutagenic or toxic to virus production. This effort will determine if viral specific glycosylase is a feasible target to exploit in the development of anti-herpes agents.
| Caradonna, S; Worrad, D; Lirette, R (1987) Isolation of a herpes simplex virus cDNA encoding the DNA repair enzyme uracil-DNA glycosylase. J Virol 61:3040-7 |
