Specific Inhibition of Formation of Transcription Complexes by a Calicheamicin Oligosaccharide: A Paradigm for the Development of Transcriptional Antagonists

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 20; pp. 9203 - 9207
• Main Authors: Ho, Steffan N., Boyer, Serge H., Schreiber, Stuart L., Danishefsky, Samuel J., Crabtree, Gerald R.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 27-09-1994; National Acad Sciences; National Academy of Sciences
• Subjects: Aminoglycosides; Animals; Anti-Bacterial Agents - pharmacology; Antibiotics, Antineoplastic - pharmacology; Base Sequence; Binding Sites; Biochemistry; Carbohydrate Conformation; Carbohydrate Sequence; Cell Line; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Deoxyribonucleic acid; DNA; DNA probes; DNA-Binding Proteins - metabolism; Enediynes; Gels; Gene Expression - drug effects; HeLa Cells; Humans; Interleukin-2 - biosynthesis; Ligands; Molecular Sequence Data; Nucleotide sequences; Oligonucleotide Probes; Oligosaccharides - pharmacology; Proteins; Reporter genes; Room temperature; T lymphocytes; Tetradecanoylphorbol Acetate - pharmacology; Transcription factors; Transcription, Genetic - drug effects; Transfection; Tumor Cells, Cultured
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.20.9203

Sequence-specific DNA ligands that antagonize DNA-protein interactions represent a potentially powerful means of modulating gene expression. Calicheamicin γ1
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 aryltetrasaccharide of calicheamicin γI
1(CLM-MG) was used to investigate the ability of glycoconjugate DNA ligands to inhibit DNA-protein interactions. CLM-MG inhibits the formation of DNA-protein complexes at micromolar concentrations in a sequence-specific manner and rapidly dissociates preformed complexes. CLM-MG also inhibits transcription in vivo with similar sequence specificity. These results suggest a strategy for the development of a class of novel biological probes and therapeutic agents.