Chemical Approaches to Control Gene Expression

Abstract

A current goal in molecular medicine is the development of new strategies to interfere with gene expression in living cells in the hope that novel therapies for human disease will result from these efforts. This review focuses on small-molecule or chemical approaches to manipulate gene expression by modulating either transcription of messenger RNA-coding genes or protein translation. The molecules under study include natural products, designed ligands, and compounds identified through functional screens of combinatorial libraries. The cellular targets for these molecules include DNA, messenger RNA, and the protein components of the transcription, RNA processing, and translational machinery. Studies with model systems have shown promise in the inhibition of both cellular and viral gene transcription and mRNA utilization. Moreover, strategies for both repression and activation of gene transcription have been described. These studies offer promise for treatment of diseases of pathogenic (viral, bacterial, etc.) and cellular origin (cancer, genetic diseases, etc.). Gene transcriptionMolecular medicine Novel therapies Therapeutic strategies CONSIDERABLE effort has been expended over the development of circular antisense deoxyoligonucleotides that are resistant to exonuclease degradation. past decade to devise methods to interfere with gene expression in living cells in the hope that therapeutic These molecules have been demonstrated to effectively downregulate the bcr-abl oncogene in a cell strategies will come from these studies. These approaches include both interference with translation of culture assay (61). Significantly, circular ODNs were shown to be more stable and more effective in downmessenger RNA into protein (with antisense oligonucleotides, peptide nucleic acids, ribozymes, deoxyriregulation of protein levels than the corresponding linear molecules. A recent advance in ribozyme techbozymes) and the direct interference with gene transcription (with triple helix-forming oligonucleotides, nology is the ability to tailor the activity of ribozymes to respond to small-molecule effectors, thus making peptide nucleic acids, decoys, and synthetic minor groove-binding ligands). Strategies for both represribozymes "allosteric molecular switches" (66). Additionally, translational control by deoxyribozymesion and activation of gene transcription have been devised and will be considered below. We will conmediated cleavage of various mRNAs has been reported (5,62,67). Among a number of recent successful centrate in this review on small-molecule or chemical approaches to manipulate gene expression at both the applications of this technology, a deoxyribozyme that targeted the translation initiation region of cMyc level of transcription and translation, but we will begin by citing recent exciting studies on other related mRNA was found to cleave its target substrate in vitro and inhibit Myc-dependent smooth muscle cell prolifmethods.Recent advances for controlling translation with eration (67). Deoxyribozymes offer the ...

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