Design of bifunctional oligonucleotide intercalator conjugates as inhibitors of gene expression.
Oligonucleotide-intercalator conjugates have been designed to control gene expression at the translational and transcriptional level. The intercalator provides an additional binding energy when the oligonucleotide binds either to a complementary sequence on a single-stranded nucleic acid or to a homopurine.homopyrimidine sequence on duplex DNA. The oligonucleotide-intercalator conjugate can arrest translation of a mRNA (the "antisense" strategy); it can block transcription of DNA (the "antigene" strategy). Some of the intercalators that we have chosen can induce irreversible reactions in their target sequence. Here we summarize the reactions that can be targeted to specific sequences of duplex DNA. Phenanthroline induces cleavage of the two strands of duplex DNA in the presence of Cu(II) and a reducing agent. Ellipticine derivatives can be used to photo-induce cleavage. Psoralen derivatives can cross-link the two strands of DNA under near UV irradiation. In all cases the chemical or photochemical reactions are targeted to a specific sequence of duplex DNA.
Helene
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Laboratoire de Biophysique, Muséum National d'Histoire Naturelle, INSERM U.201, CNRS UA.481, Paris, France.
Thuong
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D000818:Animals; D001482:Base Composition; D002460:Cell Line; D003300:Copper / Q000494:pharmacology; D004247:DNA / Q000528:radiation effects; D004261:DNA Replication / Q000187:drug effects*; D004611:Ellipticines / Q000494:pharmacology; D011564:Furocoumarins / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D007364:Intercalating Agents / Q000494:pharmacology*; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D009841:Oligonucleotides / Q000494:pharmacology*; D010618:Phenanthrolines / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects*; D013539:Simian virus 40 / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014466:Ultraviolet Rays
D004611:Ellipticines; D011564:Furocoumarins; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; D010618:Phenanthrolines; D003300:Copper; D004247:DNA