Antisense Strategies

Stanley   T.   Crooke

Abstract

Antisense technology exploits oligonucleotide analogs to bind to target RNAs via Watson-Crick by hybridization. Once bound, the antisense agent either disables or induces the degradation of the target RNA. Antisense agents may also be used to alter splicing. Developing antisense technology involves the creation of a new pharmacology. The receptors, pre- and m- RNAs, had never been studied before as sites for drug binding and action. The drugs, oligonucleotide analogs, had never made or tested as drugs before and no medicinal chemistry had been performed. The receptor binding mechanism, Watson-Crick hybridization had never been demonstrated as feasible to exploit from a pharmacological perspective. The post-receptor binding events were literally unknown and unexplored. During the past decade or more, substantial progress has been made in developing antisense pharmacology. A great deal has been learned about the basic mechanisms of antisense, the medicinal chemistry, the pharmacological, pharmacokinetic and toxicological properties of antisense molecules. Antisense technology has proven of great value in gene functionalization and target validation. With one drug marketed, Vitravene®, and approximately 20 antisense drugs in clinical development, it appears that antisense drugs may prove of value in the treatment of a wide range of diseases. In this review, the progress is summarized, the limitations of the technology discussed and the future considered.

Keywords: oligonucleotides, phosphorothioate, second generation, rnase h, rna

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