G-specific RNA-cleaving Conjugates of Short Peptides and Oligodeoxyribonucleotides

Миронова, Н. Л.; Pyshnyi, D. V.; Stadler, Dmitry V.; Prokudin, Ivan V.; Boutorine, Y. I.; Иванова, Е. М.; Zenkova, Marina A.; Groß, H.; Vlassov, Valentin V.

doi:10.1080/07391102.2006.10507084

Cited by 8 publications

(20 citation statements)

References 29 publications

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“…This suggests that, in the absence of complementarity, conjugate 5'-luc-h-9/14 behaves as a usual non-specific ribonuclease, which we observed in earlier works [76,77]. This could be attributed to some type of opportunistic cleavage during transient electrostatic interactions or imperfect hydrogen bonding between the ribonuclease and RNA substrate.…”

Section: Ribonuclease Activity Of Control Non-complementary Pocs Agaimentioning

confidence: 72%

“…Our recent data [50,51,76,77] and 5'-h-9/16 POCs, the antisense part of the conjugate was elongated from 14 to 16 nucleotide residues thus leading to shortening of the target single-stranded region of miR-21 within the hybridized complex. It was shown earlier [51] that narrowing of the RNA single-stranded target region upon binding with the conjugate may result in substantial decrease or even complete loss of catalytic activity, presumably due to reduced conformational freedom for the catalytic peptide.…”

Section: Discussionmentioning

confidence: 99%

“…via peptide C-terminus) by incorporation of the flexible linker into the conjugate structure, the specificity of chemical nucleases is switched to G-X. Previously, G-X specificity of RNA cleavage was observed for specially designed non-site selective artificial ribonuclease pep-9 [76,77] and 'dual' conjugates targeted to tRNA, both contained long flexible linkers, and the attachment via C-and N-terminus of the peptide was used [51].…”

Section: Discussionmentioning

confidence: 99%

“…Based on the experimental evidence that any considerable changes in the conjugate structure (i.e. chemical modifications of the oligonucleotide part) may lead to a significant reduction of the cleavage activity [44,76,77], in this study we decided to preserve the 'natural' sugar-phosphate backbone of the oligonucleotide recognition moieties. Our previous studies of 'dual' conjugates [51] have illuminated an importance of the conformational flexibility on their cleavage efficiency.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells

et al. 2017

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Please cite this article as: Patutina OA, Bichenkova EV, Miroshnichenko SK, Mironova NL, Trivoluzzi LT, Burusco KK, Bryce RA, Vlassov VV, Zenkova MA, miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells, Biomaterials (2017Biomaterials ( ), doi: 10.1016Biomaterials ( / j.biomaterials.2017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Ribonuclease Activity Of Control Non-complementary Pocs Agaimentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

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miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells

et al. 2017

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“…By screening experiments in which oligonucleotide and peptide fragments of the conjugates were systematically varied (18), the conjugate displaying RNase T1 cleavage specificity was identified. The conjugate consists of nonadeoxyribonucleotide GGATCTCTT and peptide (LR) 4 -G-amide, N-terminus of which is attached to the 5′-terminus of oligonucleotide via the linker group built of three deoxyribose residues.…”

Section: Resultsmentioning

confidence: 99%

RNase T1 mimicking artificial ribonuclease

Миронова

Pyshnyi

Shtadler

et al. 2007

Nucleic Acids Research

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Recently, artificial ribonucleases (aRNases)—conjugates of oligodeoxyribonucleotides and peptide (LR)4-G-amide—were designed and assessed in terms of the activity and specificity of RNA cleavage. The conjugates were shown to cleave RNA at Pyr-A and G–X sequences. Variations of oligonucleotide length and sequence, peptide and linker structure led to the development of conjugates exhibiting G–X cleavage specificity only. The most efficient catalyst is built of nonadeoxyribonucleotide of unique sequence and peptide (LR)4-G-NH2 connected by the linker of three abasic deoxyribonucleotides (conjugate pep-9). Investigation of the cleavage specificity of conjugate pep-9 showed that the compound is the first single-stranded guanine-specific aRNase, which mimics RNase T1. Rate enhancement of RNA cleavage at G–X linkages catalysed by pep-9 is 108 compared to non-catalysed reaction, pep-9 cleaves these linkages only 105-fold less efficiently than RNase T1 (kcat_RNase T1/kcat_pep-9 = 105).

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‘Dual’ peptidyl-oligonucleotide conjugates: Role of conformational flexibility in catalytic cleavage of RNA

et al. 2017

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Traditional therapeutic interventions against abnormal gene expression in disease states at the level of expressed proteins are becoming increasingly difficult due to poor selectivity, off-target effects and associated toxicity. Upstream catalytic targeting of specific RNA sequences offers an alternative platform for drug discovery to achieve more potent and selective treatment through antisense interference with disease-relevant RNAs. We report a novel class of catalytic biomaterials, comprising amphipathic RNA-cleaving peptides placed between two RNA recognition motifs, here demonstrated to target the TΨC loop and 3'- acceptor stem of tRNA. These unique peptidyl-oligonucleotide 'dual' conjugates (DCs) were created by phosphoramidate or thiol-maleimide conjugation chemistry of a TΨC-targeting oligonucleotide to the N-terminus of the amphipathic peptide sequence, followed by amide coupling of a 3'-acceptor stem-targeting oligonucleotide to the free C-terminal carboxylic acid functionality of the same peptide. Hybridization of the DCs bearing two spatially-separated recognition motifs with the target tRNA placed the peptide adjacent to a single-stranded RNA region and promoted cleavage within the 'action radius' of the catalytic peptide. Up to 100% cleavage of the target tRNA was achieved by the best candidate (i.e. DC6) within 4 h, when conformational flexibility was introduced into the linker regions between the peptide and oligonucleotide components. This study provides the strong position for future development of highly selective RNA-targeting agents that can potentially be used for disease-selective treatment at the level of messenger, micro, and genomic viral RNA.

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G-specific RNA-cleaving Conjugates of Short Peptides and Oligodeoxyribonucleotides

Cited by 8 publications

References 29 publications

miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells

miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells

RNase T1 mimicking artificial ribonuclease

‘Dual’ peptidyl-oligonucleotide conjugates: Role of conformational flexibility in catalytic cleavage of RNA

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