title: Gene silencing using a conjugate comprising Tat peptide and antisense oligonucleotide with phosphorothioate backbones.
abstract: Antisense oligonucleotides (ASOs) have a great therapeutic potential for the modulation of gene expression because of the high specificity. The major obstacles for clinical application are enzymatic degradation and low uptake into cells in vivo. In this study, we prepared the conjugate comprising Tat peptide and ASO with phosphorothioate linkages in a simple manner; azide alkyne Huisgen cycloaddition using a copper catalyst. The obtained conjugate showed a high stability in serum, compared with the conjugate with phosphodiester linkages. The conjugates with antisense for c-myb that is transcriptional factor concerning cell growth inhibited the cell proliferation in a dose dependent manner sequence-specifically. These findings suggest Tat-mediated ASOs delivery is useful for the treatment of various diseases.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1, Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka 808-0135, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Maegawa
authors.affiliation: Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1, Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka 808-0135, Japan. Electronic address: mochizuki@kitakyu-u.ac.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mochizuki
authors.affiliation: Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1, Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka 808-0135, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyamoto
authors.affiliation: Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1, Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka 808-0135, Japan; CREST, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi-shi, Saitama 332-0012, Japan. Electronic address: sakurai@kitakyu-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakurai
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057930:Click Chemistry; D015696:Gene Products, tat / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D010710:Phosphates / Q000737:chemistry; D020598:Proto-Oncogene Proteins c-myb / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015696:Gene Products, tat; D016376:Oligonucleotides, Antisense; D010455:Peptides; D010710:Phosphates; D020598:Proto-Oncogene Proteins c-myb; C083120:phosphorodithioic acid
keywords: Antisense oligonucleotide; Click Chemistry; Conjugate; Tat peptide