6.8.4 Human Safety, 142 Complement Activation, 142 Cytokines, 143 Coagulation, 143 Platelet Effects, 143 Other Toxicities, 143 6.9 Conclusions, 143

7 The Medicinal Chemistry of Oligonucleotides, 143

7.1 Introduction, 143

7.2 Heterocycle Modifications, 144

7.2.1 Pyrimidine Modifications, 144

7.2.2 Purine Modifications, 146

7.3 Oligonucleotide Conjugates, 147

7.3.1 Nuclease Stability, 147

7.3.2 Enhanced Cellular Uptake, 148

7.3.3 RNA Cleaving Groups, 149

7.3.4 RNase H Activity, 149

7.3.5 in Vivo Effects, 149

7.4 Sugar Modifications, 150

7.4.1 2'-Modified Oligonucleotides with Ability to Activate RNase H, 152

7.5 Backbone Modifications, 152

7.6 Summary, 153

8 2'-0-(2-Methoxyethyl) Chimeras: Second-Generation Antisense Drugs, 153

9 Conclusions, 155

10 Abbreviations, 155

11 Acknowledgments, 156

1.1 Definition

During the past decade, antisense technology has matured. Today, antisense technology is generally accepted as a broadly useful method for gene functionalization and target validation. Further, with Vitravene's approval by regulatory agencies around the world (making it the first antisense drug to be commercialized), the emerging data showing the activity of a number of antisense drugs in clinical trials, and the overwhelming evidence from studies in animals, the potential of antisense as a therapeutic technology is now better appreciated.

The purposes of this review are to provide a summary of the progress in the technology, to address its role in gene functionalization and target validation as well as therapeutics, and to consider the limitations of the technology and a few of the many questions that remain to be answered.

Antisense technology exploits oligonucleotide analogs (typically 15-20 nucleotides) to bind to cognate RNA sequences through Watson-Crick hybridization, resulting in the destruction or disablement of the target RNA. Thus antisense technology represents a "new pharmacology." The receptor, messenger RNA (mRNA), has never before been considered in the context of drug-receptor interactions. Before the advent of antisense technology, no medicinal chemistry had been practiced on the putative "drugs," oligonucleotides. The basis of the drug-receptor interaction, Watson-Crick hybridization, had never been considered as a potential binding event for drugs and put into a pharmacological context. Finally, postbinding events such as recruitment of nucleases to degrade the receptor RNA had never been considered from a pharmacological perspective.

A key to understanding antisense technology is to consider it in a pharmacological context. It is essential to understand the structure, function, and metabolism of the receptors for these drugs. As with any of the class of drugs, it is essential to consider the effects of antisense oligonucleotides in the context of dose-response curves. It is essential to consider the future in the context of advances in antisense biology and medicinal chemistry that result in improved pharmacological behaviors.

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