5-SUBSTITUTED-2'-DEOXYURIDINES AS ANTI-HSV-1 AGENTS - SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP

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-l 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.