Abstract
Background:
Recently, the synthesis and antiviral activity of a series of 2'-fluoro derivatives of the most potent anti-varicella zoster virus (VZV) agent reported to date, the bicyclic nucleoside analogue Cf1743, have been reported.
Methods:
Here, we present molecular modelling studies for the interaction of these compounds with VZV-encoded thymidine kinase (TK) and we report the synthesis of a series of phosphoramidate ProTides of these compounds designed to bypass the nucleoside kinase dependence of the parent nucleoside analogues.
Results:
The phosphoramidate prodrugs were equally effective as their parent compounds against VZV in cell culture, but lost antiviral potency against TK-deficient VZV strains.
Conclusions:
ProTide-based kinase bypass is not successful in this case.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / chemical synthesis
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Amides / chemistry*
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Amides / metabolism
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Amides / pharmacology*
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Antiviral Agents / chemical synthesis
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Antiviral Agents / chemistry*
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Antiviral Agents / metabolism
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Antiviral Agents / pharmacology*
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Cell Line
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Fluorine / chemistry*
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Herpesvirus 3, Human / drug effects*
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Herpesvirus 3, Human / enzymology
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Models, Molecular
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Phosphoric Acids / chemical synthesis
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Phosphoric Acids / chemistry*
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Phosphoric Acids / metabolism
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Phosphoric Acids / pharmacology*
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Protein Conformation
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Pyrimidine Nucleosides / chemistry*
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Pyrimidine Nucleosides / pharmacology
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Thymidine Kinase / chemistry
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Thymidine Kinase / metabolism
Substances
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Amides
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Antiviral Agents
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Cf 1743
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Phosphoric Acids
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Pyrimidine Nucleosides
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Fluorine
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phosphoramidic acid
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Thymidine Kinase