Chapter 62: Antiviral Agents (Nonretroviral)

INTRODUCTION

Most antivirals currently available in the U.S. have been developed and approved in the last 35 years. This flurry of activity was driven by successes in rational drug design and approval that began with the antiherpesvirus nucleoside analogue acyclovir (Elion, 1986), whose discovery and development resulted in the awarding of the 1988 Nobel Prize in Physiology/Medicine to Gertrude Elion and George Hitchings, an award they shared with James Black (see Chapter 43) “for their discoveries of important principles for drug treatment.” Because viruses are obligatory intracellular microorganisms and rely on host biosynthetic machinery to reproduce, there were doubts about the possibility of developing antiviral drugs with selective toxicity, but those doubts have long been erased. Viruses are now obvious targets for effective antimicrobial chemotherapy, and it is certain that the number of available agents in this category will continue to increase. Indeed, the recent development of agents that target the viral protein NS5A has revolutionized treatment of infections of hepatitis B virus (HBV) and hepatitis C virus (HCV), and these agents are now allotted a chapter of their own, Chapter 63. Chapter 64 describes chemotherapy for retroviruses. This chapter covers antiviral agents for nonretroviral infections other than HBV and HCV.

ABBREVIATIONS

VIRAL REPLICATION AND DRUG TARGETS

Viruses are simple microorganisms that consist of either double- or single-stranded DNA or RNA enclosed in a protein coat called a capsid. Some viruses also possess a lipid envelope derived from the infected host cell, which, like the capsid, may contain antigenic glycoproteins. Effective antiviral agents inhibit virus-specific replicative events or preferentially inhibit virus-directed rather than host cell–directed nucleic acid or protein synthesis (Table 62–1). Host cell molecules that are essential to viral replication also offer targets for intervention. Figure 62–1 gives a schematic diagram of the replicative cycle of typical DNA and RNA viruses with the sites of antiviral drugs indicated.