SPECIFIC-INHIBITION OF FORMATION OF TRANSCRIPTION COMPLEXES BY A CALICHEAMICIN OLIGOSACCHARIDE - A PARADIGM FOR THE DEVELOPMENT OF TRANSCRIPTIONAL ANTAGONISTS

Sequence-specific DNA ligands that antagonize DNA-protein interactions represent a potentially powerful means of modulating gene expression. Calicheamicin gamma 1(I), a member of the DNA-cleaving enediyne class of anticancer antibiotics, binds to specific DNA sequences through an aryltetrasaccharide domain. To take advantage of this unique sequence -specific recognition capability, the methyl glycoside of the aryltetr asaccharide of calicheamicin gamma 1(I) (CLM-MG) was used to investiga te the ability of glycoconjugate DNA ligands to inhibit DNA-protein in teractions. CLM-MG inhibits the formation of DNA-protein complexes at micromolar concentrations in a sequence-specific manner and rapidly di ssociates preformed complexes. CLM-MG also inhibits transcription in v ivo with similar sequence specificity. These results suggest a strateg y for the development of a class of novel biological probes and therap eutic agents.