Antisense Inhibition of Virus Infections

This chapter summarizes the new approaches to identify novel antiviral drug targets and to develop novel antiviral strategies. The chapter also reviews genetic pharmacology as it relates to antiviral antisense research and drug development. Antisense oligonucleotides are selective compounds by virtue of their interaction with specific segments of RNA. For potential antivirals, identification of appropriate target RNA sequences for antisense oligonucleotides is performed at two levels: the optimal gene within the virus, and the optimal sequence within the RNA. The importance of these oligonucleotide modifications in designing effective drugs is just now being evaluated, both in animal model systems and in the clinic. The first generation of widely used antisense oligonucleotides has been the phosphorothioate (PS) compounds and a body of data on biodistribution, pharmacokinetics, and metabolism in animals and in humans is now available. Since the identification and sequencing of human immunodeficiency virus (HIV), there has been a strong interest in identifying a potent oligonucleotide inhibitor that would have the potential for development as a therapy for acquired immunodeficiency syndrome (AIDS). Numerous phosphorothioate oligonucleotides, with no apparent antisense sequence specificity, can have an anti-herpes simplex virus (HSV) effect. Oligonucleotides can be effective anti-influenza agents in cell culture assays. Hepatitis B virus (HBV) X protein that is a transactivator has been also reported to be targeted successfully by antisense oligonucleotides in vivo. Several of picornaviruses have been targets for antisense oligonucleotide inhibition, and the studies demonstrate the versatility of the antisense approach. However, the fact that oligonucleotides may contribute numerous mechanisms toward the antiviral activity, in addition to the antisense mechanism, may in some cases be an asset in the pursuit of clinically useful antiviral drugs.