Antisense oligodeoxynucleotides as antiviral agents

Abstract

A new paradigm is needed for the development of antiviral drugs. Most drugs that have been developed work according to a paradigm in which a small organic molecule, often of natural origin, fits into an enzyme active site. This interaction usually requires 3-4 hydrogen bonds that confer most of the specificity. Such drugs are discovered rarely in random screening programs. Another paradigm is the incorporation into the putative drug molecule of a higher degree of information, that ensures greater specificity through more hydrogen bonds. Perhaps, the most specific interaction that has been discovered in biology is the Watson-Crick base-pairing found in DNA duplexes. This is the basis of the genetic code, that must be stable, selective and reproducible. It has also evolved over millennia. An informational drug might have encoded in it the complementary, or antisense, base sequence, to a target cellular nucleic acid sequence. In practical terms, this means using an oligodeoxynucleotide targeted at a sequence in the mRNA of the gene to bring about translation arrest (Cohen, 1989a). This term was originally coined in relation to the expression in prokaryotes of antisense mRNA that is produced naturally as a regulatory process in relation to the expressed, or sense, mRNA (Inouye, 1988). The strategy of producing antisense mRNA through the medium of a plasmid vector has been used to regulate sense