Oligonucleotide Inhibitors of Gene Expression in Living Cells: New Opportunities in Drug Design

This chapter describes some of the oligomers and experiments in which they have been used to control gene expression at the messenger RNA (mRNA) level, particularly in living cells. It appears that this concept could be exploited to develop clinically useful drugs to control the growth of viruses or malignant cells. Present day drugs that bind or intercalate in the minor groove of DNA have their limited ability to recognize specific nucleic sequences. In that way, they cannot take full advantage of the sequence information available in DNA, and thus are unable to inhibit expression of specific genes. The preparation, introduction, and expression of anti-sense RNAs require rather sophisticated molecular biology techniques. They can be prepared in the laboratory and then introduced into cells by microinjection or expressed in cells after transfection with plasmids carrying an anti-sense gene. The control of gene expression can, in theory, be achieved by single-stranded nucleic acids, that can specifically read complementary mRNA sequences via Watson–Crick base-pairing interactions. There exists a simpler approach that involves the use of short anti-sense oligonucleotides or oligonucleotide analogs prepared by chemical synthesis. There are three types of oligonucleotides that are oligodeoxyribonucleotides, oligomers having modified sugar–phosphate backbones, and oligomers derivatized with specific functional groups. Little is known about the stability, distribution, acute and/or chronic toxicity, or immunogenicity of compounds in vivo belonging to the anti-sense oligonucleotides or oligonucleotide analogs class. The promising results obtained in cell culture studies suggest that anti-sense oligonucleotide analogs offer a unique approach for the rational design of drug.