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INTRODUCTION

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Most antivirals currently available in the U.S. have been developed and approved in the last 25 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 a Nobel Prize to Gertrude Elion and George Hitchings in 1988. 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 HVB and HVC, and these agents are now allotted a chapter of their own, Chapter 63. Chapter 64 describes chemotherapy for retroviruses. This present chapter covers antiviral agents for nonretroviral infections other than HVB and HVC.

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ABBREVIATIONS

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Abbreviations

ADME: absorption, distribution, metabolism, excretion

AIDS: acquired immune deficiency syndrome

AUC: area under the curve

CAPD: chronic ambulatory peritoneal dialysis

CDC: Centers for Disease Control and Prevention

cDNA: complementary DNA

CLcr: creatinine clearance

CMV: cytomegalovirus

CNS: central nervous system

CP: plasma concentration (of a drug, usually)

cRNA: complementary RNA

CSF: cerebrospinal fluid

CYP: cytochrome P450 isozyme

DNAp: DNA polymerase

EBV: Epstein-Barr virus

EIND: emergency investigational new drug

FDA: Food and Drug Administration

G-CSF: granulocyte colony-stimulating factor

GI: gastrointestinal

HBV: hepatitis B virus

HCV: hepatitis c virus

HHV-6: human herpesvirus 6

HIV: human immunodeficiency virus

HSV: herpes simplex virus

IFN: interferon

mRNA: messenger RNA

NSAID: nonsteroidal anti-inflammatory drug

RNAp: RNA polymerase

RNP: ribonuclear protein

SARS: severe acute respiratory syndrome

TK: thymidine kinase

vRNA: viral RNA

VZV: varicella zoster virus

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VIRAL REPLICATION AND DRUG TARGETS

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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 anti-viral drugs indicated.

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Figure 62–1

Replicative cycles of DNA (A) and RNA (B) viruses. The replicative cycles of herpesvirus (A) and influenza (B) are examples of DNA-encoded and RNA-encoded viruses, respectively. Sites of action of antiviral agents also are shown. The symbol ⊣ indicates a block to virus growth. ...

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