TRANSCRIPTION FACTORS - TARGETS FOR NEW DESIGNER DRUGS

Many diseases are the result of aberrant regulation of cell and tissue -specific gene expression. At the molecular level they are often chara cterised by disruption of the cell cycle through inappropriate activat ion or inactivation of key regulatory proteins, termed nuclear transcr iption factors (NFs). NF activation is modulated by several potent cla sses of drug, including steroids, retinoids, and immunosuppressants li ke cyclosporin A and FK506. While such drugs have wide application, th ey lack specificity and produce undesired side-effects. Recently, howe ver, the three-dimensional structures of some NFs, as well as their mo lecular interactions with DNA targets, have been reported and several biochemical pathways involved in altered NF function identified. This is setting the stage for a rational approach to the design of drugs th at act in a tissue- or disease-specific manner, target particular gene s and proteins, and will combine increased efficacy with reduced side- effects.