title: miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells.
abstract: MicroRNAs (miRNAs) are active regulators in malignant growth and constitute potential targets for anticancer therapy. Consequently, considerable effort has focused on identifying effective ways to modulate aberrant miRNA expression. Here we introduce and assess a novel type of chemically engineered biomaterial capable of cleaving specific miRNA sequences, i.e. miRNA-specific artificial ribonucleases (hereafter 'miRNase'). The miRNase template presented here consists of the catalytic peptide Acetyl-[(LeuArg)2Gly]2covalently attached to a miRNA-targeting oligonucleotide, which can be linear or hairpin. The peptide C-terminus is conjugated to an aminohexyl linker located at either the 3'- or 5'-end of the oligonucleotide. The cleavage efficacy, structural aspects of cleavage and biological relevance of a set of these designed miRNases was assayed with respect to highly oncogenic miR-21. Several miRNases demonstrated effective site-selective cleavage of miR-21 exclusively at G-X bonds. One of the most efficient miRNase was shown to specifically inhibit miR-21 in lymphosarcoma cells and lead to a reduction in their proliferative activity. This report provides the first experimental evidence that metallo-independent peptide-oligonucleotide chemical ribonucleases are able to effectively and selectively down-regulate oncogenic miRNA in tumour cells, thus suggesting their potential in development of novel therapeutics aimed at overcoming overexpression of disease-related miRNAs.
authors.affiliation: Laboratory of Nucleic Acids Biochemistry, Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev ave., 8, Novosibirsk, 630090, Russia.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Patutina
authors.affiliation: School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK. Electronic address: elena.v.bichenkova@manchester.ac.uk.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Bichenkova
authors.affiliation: Laboratory of Nucleic Acids Biochemistry, Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev ave., 8, Novosibirsk, 630090, Russia.
authors.forename: Svetlana K
authors.initials: SK
authors.lastname: Miroshnichenko
authors.affiliation: Laboratory of Nucleic Acids Biochemistry, Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev ave., 8, Novosibirsk, 630090, Russia.
authors.forename: Nadezhda L
authors.initials: NL
authors.lastname: Mironova
authors.affiliation: School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Linda T
authors.initials: LT
authors.lastname: Trivoluzzi
authors.affiliation: School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Kepa K
authors.initials: KK
authors.lastname: Burusco
authors.affiliation: School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
authors.affiliation: Laboratory of Nucleic Acids Biochemistry, Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev ave., 8, Novosibirsk, 630090, Russia.
authors.forename: Valentin V
authors.initials: VV
authors.lastname: Vlassov
authors.affiliation: Laboratory of Nucleic Acids Biochemistry, Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev ave., 8, Novosibirsk, 630090, Russia. Electronic address: marzen@niboch.nsc.ru.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Zenkova
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D012260:Ribonucleases / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; D010455:Peptides; D012260:Ribonucleases
keywords: Anti-miRNA therapy; Antisense oligonucleotides; Oncogenic miRNA; Peptide-oligonucleotide conjugates; RNA cleavage; miR-21