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Title: Study of antiviral resistance to helicase-primase inhibitors of herpes simplex virus type 1
Author: Biswas, S.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2008
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The herpes simplex virus (HSV) helicase-primase complex represents a relatively new target for inhibition by non-nucleoside antiviral compounds. A claimed advantage of helicase-primase inhibitors (HPIs) is the reported low frequency of drug-resistance (approx. 10-6) in tissue culture. It was confirmed in this study that one HPI, the thiozoleamide, known as “BAY 57-1293” is superior to the nucleoside analogue acyclovir against HSV-1 in tissue culture. Furthermore, BAY 57-1293 showed more potent therapeutic antiviral activity than the nucleoside analogue prodrug, famciclovir in BALB/c mice, infected with HSV-1. It was observed that drug-resistant variants could be readily selected by culturing HSV-1 in the presence of BAY 57-1293. The different resistant viruses obtained during this study were stable and showed resistance to BAY 57-1293 varying from approx. 15-fold to >5,000-fold. Several viruses were sequenced to define the genetic lesions. The putative resistance mutations all mapped to either the HSV-1 UL5 helicase or UL52 primase protein. A marker-transfer strategy was established to confirm the role of particular amino acid substitutions in drug-resistance and their effects on other biological properties. Two generally-defined BAY 57-1293 resistant mutants were characterized for cross-resistance to an alternative HPI (BILS 22 BS); growth properties in tissue culture; and pathogenicity in a murine HSV-1 infection model. It was established from these experiments that single mutations close to a predicted functional domain of the UL5 helicase protein account for co-resistance to both HPI, suggesting that both interact with UL5 helicase. The same drug-resistance mutations were also associated with changes (increase or decrease) to virus growth in tissue culture and pathogenicity. Hypotheses are developed to explain possible differences between HPI concerning their interaction with the viral helicase-primase complex. The studies described in this thesis may have a bearing on the potential for HPI-resistance to subvert effective therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available