Nucleoside and pyrophosphate analogues are currently in use to treat infection with Human herpesvirus 1 (HSV-1). Both series of compounds exert their activity by inhibition of the viral DNA polymerase either directly, or after anabolic phosphorylation. As the X-ray structure of the viral-specific DNA polymerase is not known, it is difficult to design a nucleoside or non-nucleoside antiviral agent which specifically inhibits this enzyme. Therefore, alternative strategies have relied on extensive structure activity relationship studies of anti-HSV-1 agents in an endeavour to understand the essential structural requirements for activity and hence the design of drugs with increased selectivity. A virus-specific enzyme which plays a crucial role in the selective activation of nucleoside analogues is thymidine kinase. Present knowledge regarding the specificity of herpesvirus thymidine kinase for its 5-substituted-2′-deoxyuridine substrates is reviewed herein.
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