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Oligo(alpha-deoxynucleotide)s covalently linked to intercalating agents: differential binding to ribo- and deoxyribopolynucleotides and stability towards nuclease digestion.
Author(s) -
Nguyen T. Thuong,
Ulysse Asseline,
Véronique Roig,
Masashi Takasugi,
Claude Hélène
Publication year - 1987
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.84.15.5129
Subject(s) - acridine , deoxyribose , oligonucleotide , nuclease , anomer , covalent bond , stereochemistry , chemistry , dna , biochemistry , organic chemistry
An octathymidylate was synthesized with the alpha anomer of thymidine instead of the naturally occurring beta anomer. This oligonucleotide binds to complementary sequences containing beta-nucleosides. Binding to ribose-containing oligomers and polymers is much stronger than binding to deoxyribose-containing analogs. A derivative of acridine (9-amino-6-chloro-2-methoxyacridine) was covalently attached either to the 5' phosphate or to the 3' phosphate of the alpha-octathymidylate. A pentamethylene linker was used to bridge the phosphate group and the 9-amino group of the acridine derivative. In both cases the complexes with the complementary sequences were strongly stabilized due to the additional binding energy provided by intercalation of the acridine ring within the miniduplex structure formed by the oligonucleotide with its target sequence. The acridine-substituted alpha-oligothymidylates did not lose their discrimination between ribose and deoxyribose-containing complementary sequences. The alpha-oligothymidylates were much more resistant towards endonucleases than their beta analogs, independently of whether they were linked to the acridine derivative. Acridine substitution provided additional protection against the corresponding exonucleases. alpha-Oligodeoxynucleotides covalently linked or not to intercalating agents represent families of molecules that open possibilities to block mRNA translation or viral RNA expression in vitro and in vivo.

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