Antiviral Treatment: From Concept to Reality

Abstract

The initial development of antiviral compounds was slow, with the first clinical antiviral agent not available until the 1960s. Early development was hindered by the lack of understanding of virus life-cycles and the absence of an assay system for antiviral activity. The appearance of the first assay system, the fertilized egg yolk sac, led to the identification of methisazone. This was the first antiviral agent to be used clinically. The improvement in antiviral assay systems, and the start of directed research programmes led to the development of the first antiherpes agents idoxuridine, trifluorothymidine (TFT) and vidarabine. However, all of these agents were associated with significant adverse effects. Antiherpes therapy took a major step forward with the development of the acyclic nucleoside analogue, aciclovir. Aciclovir is much more potent than previous antiherpesvirus agents. Its mode of action results in selectivity for herpesvirus-infected cells, thus significantly reducing the side-effects seen with earlier agents. Because of this, it became the standard therapy for herpes simplex virus type 1 (HSV-1), HSV-2 and varicella zoster virus infections. However, the bioavailability of oral aciclovir is poor, requiring high and frequent doses. This led to the search for better absorbed agents and to the development of two prodrugs, famciclovir and valaciclovir. Both famciclovir and valaciclovir offer much improved bioavailability of the nucleosides penciclovir and aciclovir, compared with aciclovir. Once in the body the conversion of valaciclovir to aciclovir means that the two agents have similar pharmacokinetic properties. Similarly, famciclovir is converted to penciclovir in the body. Penciclovir, when phosphorylated in virus-infected cells, persists within the cell for a much longer period than aciclovir triphosphate. Over the last 10 years we have seen an acceleration in the development of antiviral agents and some major advances in antiviral therapy. Many challenges, however, still lie ahead.