Antisense Oligonucleotides as Potential Drugs

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Antisense technology is a novel method for drug discovery and drug development. Antisense oligodeoxynucleotides (ODN) work at the genetic level by inhibiting the translation of disease-causing proteins. Proteins are the key players in the etiology of diseases. Especially for cancer and viral infections, the antisense technology shows promise. The underlying mechanism of this approach is to sequence-specifically interfere in the genetic flow at the mRNA level. This molecular recognition is believed to rely on Watson–Crick base pairing between the mRNA and the antisense oligonucleotide. Different modes of action are to be considered. The ODNs can either simply function as a steric block to interfere with the ribosomal translation or induce the action of particular RNases to destroy the mRNA in the hybrid formed with the ODN. In addition to this pharmacodynamic consideration, pharmacokinetic processes are important for optimal drug activity. Key points are the mode of delivery of the ODNs to the patient, to assure that the target is reached in the cells or organs of concern. The synthesis of the oligonucleotides has to be straightforward, economic, and reliable. The ODNs should be fairly metabolically stable, possess high affinity to the target, be nontoxic, and preferentially orally available. The first generation of ODNs are the phosphorothioate analogues that have been extensively tested. However, further developments of analogues for improvement are actively pursued. This article will feature the design of oligos, their synthesis, modifications, and a discussion of the mechanisms of action. The ODN application will be illustrated with some selected examples, with the emphasis on those that are in clinical trials. Keywords: Anneal (hybridize); Antisense; Ribozyme; RNase H; RNAi; Phosphorothioate; Backbone