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 1I, 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 gamma 1I (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.
Ho
S N
SN
Department of Pathology, Stanford University School of Medicine, CA 94305.
Boyer
S H
SH
Schreiber
S L
SL
Danishefsky
S J
SJ
Crabtree
G R
GR
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D053281:Enediynes; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D009844:Oligosaccharides / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D053281:Enediynes; D007376:Interleukin-2; D015345:Oligonucleotide Probes; D009844:Oligosaccharides; C055955:calicheamicin gamma(1)I; D013755:Tetradecanoylphorbol Acetate