title: Controlled intracellular localization and enhanced antisense effect of oligonucleotides by chemical conjugation.
abstract: Oligonucleotides can be covalently linked to peptides composed of any sequence of amino acids by solid phase fragment condensation. The peptides incorporated into the conjugates include nuclear localizing signals (NLS), nuclear export signals (NES), membrane fusion domain of some viral proteins and some designed peptides with amphipathic character. Evaluation of biological properties of DNA-peptide conjugates indicated that (a) the conjugates could bind to target RNA and dsDNA with increased affinity, (b) the conjugates were more resistant to cellular nuclease degradation, (c) the conjugate-RNA hybrids could activate RNase H as effectively as native oligonucleotides, (d) the conjugates with fusion peptides showed largely enhanced cellular uptake, (e) the conjugates with NLS could be predominantly delivered into the cell nucleus, (f) the conjugates with NES could be localized in the cytoplasm. As a result, antisense oligonucleotides conjugated with NLS could inhibit human telomerase in human leukemia cells much more strongly than phosphorothioate oligonucleotides.
authors.affiliation: On-site Sensing and Diagnosis Research Laboratory, National Institute for Advanced Industrial Science and Technology (AIST) Kyushu, 807-1 Shuku-machi, Tosu, Saga 841-0052, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kubo
authors.forename: Zhivko
authors.initials: Z
authors.lastname: Zhelev
authors.forename: Rumiana
authors.initials: R
authors.lastname: Bakalova
authors.forename: Bakalova
authors.initials: B
authors.lastname: Rumiana
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohba
authors.forename: Keiko
authors.initials: K
authors.lastname: Doi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D019098:Telomerase / Q000037:antagonists & inhibitors
chemical_list: D016376:Oligonucleotides, Antisense; D004247:DNA; D019098:Telomerase