Research into the molecular biology of herpes replication in recent years has revealed novel targets for drug development (Fig. 68.1). The characterization and functional assay of these targets have been facilitated by advancements in gene expression, protein purification, proteonomics, bioinformatics, and efficient robotic screening technologies. The pipeline for new herpes drugs has been expanding as drug candidates have evolved more rapidly due to improvements in chemical synthesis (i.e., combinatorial and parallel synthesis methods), and with aids for drug design (X-ray crystallography, in silico computer modeling tools, as well as chemoinformatics). Many new herpes inhibitors have been reported, and most of these possess novel modes of actions. Several have entered clinical evaluation, with some later discontinued because of safety issues. This chapter will describe promising drug candidates in early development that appear to act at individual steps of the viral replication cycle, and focus on those that have the most potential for success (Table 68.1).

The chemotherapy of herpes infections was markedly advanced by the discovery of the first, highly selective antiherpetic agent, acyclovir (ACV, Zovirax®; [9-(2-hydroxyethoxymethyl)guanine]) (Elion et al., 1977). Since the introduction of this agent, there has been only incremental progress in new drug approvals for the myriad of diseases caused by this family of diverse pathogens. The drugs approved since the introduction of ACV include valacyclovir (VACV, Valtrex®, the L-valine ester prodrug of ACV, penciclovir (PCV; [9-(4-hydroxy-3-hydroxymethylbutyl-1-yl) guanine]), a related nucleoside analogue with a similar basis for drug action against HSV and VZV, and its prodrug, famciclovir (FCV, Famvir®).