title: Peptidyl-oligonucleotide conjugates demonstrate efficient cleavage of RNA in a sequence-specific manner.
abstract: Described here is a new class of peptidyl-oligonucleotide conjugates (POCs) which show efficient cleavage of a target RNA in a sequence-specific manner. Through phosphoramidate attachment of a 17-mer TΨC-targeting oligonucleotide to amphiphilic peptide sequences containing leucine, arginine, and glycine, zero-linker conjugates are created which exhibit targeted phosphodiester cleavage under physiological conditions. tRNA(Phe) from brewer's yeast was used as a model target sequence in order to probe different structural variants of POCs in terms of selective TΨC-arm directed cleavage. Almost quantitative (97-100%) sequence-specific tRNA cleavage is observed for several POCs over a 24 h period with a reaction half-life of less than 1 h. Nontargeted cleavage of tRNA(Phe) or HIV-1 RNA is absent. Structure-activity relationships reveal that removal of the peptide's central glycine residue significantly decreases tRNA cleavage activity; however, this can be entirely restored through replacement of the peptide's C-terminal carboxylic acid group with the carboxamide functionality. Truncation of the catalytic peptide also has a detrimental effect on POC activity. Based on the encouraging results presented, POCs could be further developed with the aim of creating useful tools for molecular biology or novel therapeutics targeting specific messenger, miRNA, and genomic viral RNA sequences.
authors.affiliation: †Manchester Pharmacy School, University of Manchester, Oxford Road, Manchester, United Kingdom, M13 9PT.
authors.forename: Aled
authors.initials: A
authors.lastname: Williams
authors.affiliation: ‡Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Laurentiev Avenue, 630090, Novosibirsk, Russia.
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Staroseletz
authors.affiliation: ‡Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Laurentiev Avenue, 630090, Novosibirsk, Russia.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Zenkova
authors.affiliation: §Peptisyntha S.A., 310 Rue de Ransbeek, 1120 Brussels, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: Jeannin
authors.affiliation: †Manchester Pharmacy School, University of Manchester, Oxford Road, Manchester, United Kingdom, M13 9PT.
authors.forename: Harmesh
authors.initials: H
authors.lastname: Aojula
authors.affiliation: †Manchester Pharmacy School, University of Manchester, Oxford Road, Manchester, United Kingdom, M13 9PT.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Bichenkova
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D012331:RNA, Fungal / Q000737:chemistry / Q000378:metabolism*; D012343:RNA, Transfer / Q000737:chemistry / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D009841:Oligonucleotides; D010455:Peptides; D012331:RNA, Fungal; D012343:RNA, Transfer