Oligonucléotides "sens" : ligands rationnels des facteurs de transcription

Abstract

Transcriptional control in eukaryotes results from the interplay between cis-acting DNA sequences in promoters, enhancers or silencers and trans-acting regulatory proteins (transcription factors). Transcription factors exhibit a great diversity, strong affinity and high specificity for their binding sites on DNA, and their effects on gene expression are very specific. Moreover, transcription factors are implicated in the development of numerous human diseases.These features make them attractive targets for therapeutic research. One possible approach to decrease the availability of a DNA-binding transcription factor, and thereby inhibit or activate the expression of a specific gene, is to titrate the targeted protein with a double- stranded oligonucleotide containing its specific DNA binding site. This oligonucleotide-based sense strategy may thus provide a rational therapeutic tool to control genes, the expression of which is specifically involved in viral diseases or cancer. Dumbbell oligonucleotides are closed molecules in which the double-stranded binding sequence is connected at both ends by loops. Dumbbells combine proper binding of transcription factors together with an increased stability towards nuclease degradation. Nanomolar concentrations of these substances have been shown to strongly inhibit gene expression with high specificity in ex vivo assays These properties make them particularly attractive as transcription factor <<traps>>. Dumbbell oligonucleotides offer a new and efficient approach for the exogenous control of gene expression.