Elucidating biochemical mechanisms of resistance to herpesvirus polymerase inhibitors using a phage-based ortholog

The selection of resistance to compounds that target the DNA polymerase of various members of the herpesviridae family can compromise therapy. However, due to the lack of relevant crystal structures, the underlying biochemical mechanisms remain elusive. To address this problem, we have recently engi...

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Bibliographic Details
Published in:Antiviral therapy 2014-01, Vol.19, p.A51-A51
Main Authors: Bennett, N, Bennett, L, McCormick, S, Auger, A, Tchesnokov, E, Gotte, M
Format: Article
Language:English
Subjects:
Herpesviridae
Herpesvirus
Human cytomegalovirus
Online Access:Get full text
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Summary:The selection of resistance to compounds that target the DNA polymerase of various members of the herpesviridae family can compromise therapy. However, due to the lack of relevant crystal structures, the underlying biochemical mechanisms remain elusive. To address this problem, we have recently engineered a chimeric polymerase enzyme composed of an orthologous bacteriophage (RB69) backbone that facilitates its purification, and an active site derived from the human cytomegalovirus (HCMV) polymerase that is sensitive to antiviral drugs. We successfully crystallized a complex with nucleic acid substrate and the broad spectrum antiviral phosphonoformic acid (PFA). The structure serves as model for the study of mechanisms associated with active site inhibition and drug resistance. The data validate the phage-virus chimera as a surrogate system for the study of mechanisms associated with resistance to anti-herpetic, active site polymerase inhibitors.
ISSN:1359-6535