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Dual miRNases for Triple Incision of miRNA Target: Design Concept and Catalytic Performance

Irreversible destruction of disease-associated regulatory RNA sequences offers exciting opportunities for safe and powerful therapeutic interventions against human pathophysiology. In 2017, for the first time we introduced miRNAses–miRNA-targeted conjugates of a catalytic peptide and oligonucleotide...

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Autores principales: Patutina, Olga, Chiglintseva, Daria, Bichenkova, Elena, Gaponova, Svetlana, Mironova, Nadezhda, Vlassov, Valentin, Zenkova, Marina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287882/
https://www.ncbi.nlm.nih.gov/pubmed/32466298
http://dx.doi.org/10.3390/molecules25102459
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author Patutina, Olga
Chiglintseva, Daria
Bichenkova, Elena
Gaponova, Svetlana
Mironova, Nadezhda
Vlassov, Valentin
Zenkova, Marina
author_facet Patutina, Olga
Chiglintseva, Daria
Bichenkova, Elena
Gaponova, Svetlana
Mironova, Nadezhda
Vlassov, Valentin
Zenkova, Marina
author_sort Patutina, Olga
collection PubMed
description Irreversible destruction of disease-associated regulatory RNA sequences offers exciting opportunities for safe and powerful therapeutic interventions against human pathophysiology. In 2017, for the first time we introduced miRNAses–miRNA-targeted conjugates of a catalytic peptide and oligonucleotide capable of cleaving an miRNA target. Herein, we report the development of Dual miRNases against oncogenic miR-21, miR-155, miR-17 and miR-18a, each containing the catalytic peptide placed in-between two short miRNA-targeted oligodeoxyribonucleotide recognition motifs. Substitution of adenines with 2-aminoadenines in the sequence of oligonucleotide “shoulders” of the Dual miRNase significantly enhanced the efficiency of hybridization with the miRNA target. It was shown that sequence-specific cleavage of the target by miRNase proceeded metal-independently at pH optimum 5.5–7.5 with an efficiency varying from 15% to 85%, depending on the miRNA sequence. A distinct advantage of the engineered nucleases is their ability to additionally recruit RNase H and cut miRNA at three different locations. Such cleavage proceeds at the central part by Dual miRNase, and at the 5′- and 3′-regions by RNase H, which significantly increases the efficiency of miRNA degradation. Due to increased activity at lowered pH Dual miRNases could provide an additional advantage in acidic tumor conditions and may be considered as efficient tumor-selective RNA-targeted therapeutic.
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spelling pubmed-72878822020-06-15 Dual miRNases for Triple Incision of miRNA Target: Design Concept and Catalytic Performance Patutina, Olga Chiglintseva, Daria Bichenkova, Elena Gaponova, Svetlana Mironova, Nadezhda Vlassov, Valentin Zenkova, Marina Molecules Article Irreversible destruction of disease-associated regulatory RNA sequences offers exciting opportunities for safe and powerful therapeutic interventions against human pathophysiology. In 2017, for the first time we introduced miRNAses–miRNA-targeted conjugates of a catalytic peptide and oligonucleotide capable of cleaving an miRNA target. Herein, we report the development of Dual miRNases against oncogenic miR-21, miR-155, miR-17 and miR-18a, each containing the catalytic peptide placed in-between two short miRNA-targeted oligodeoxyribonucleotide recognition motifs. Substitution of adenines with 2-aminoadenines in the sequence of oligonucleotide “shoulders” of the Dual miRNase significantly enhanced the efficiency of hybridization with the miRNA target. It was shown that sequence-specific cleavage of the target by miRNase proceeded metal-independently at pH optimum 5.5–7.5 with an efficiency varying from 15% to 85%, depending on the miRNA sequence. A distinct advantage of the engineered nucleases is their ability to additionally recruit RNase H and cut miRNA at three different locations. Such cleavage proceeds at the central part by Dual miRNase, and at the 5′- and 3′-regions by RNase H, which significantly increases the efficiency of miRNA degradation. Due to increased activity at lowered pH Dual miRNases could provide an additional advantage in acidic tumor conditions and may be considered as efficient tumor-selective RNA-targeted therapeutic. MDPI 2020-05-25 /pmc/articles/PMC7287882/ /pubmed/32466298 http://dx.doi.org/10.3390/molecules25102459 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Patutina, Olga
Chiglintseva, Daria
Bichenkova, Elena
Gaponova, Svetlana
Mironova, Nadezhda
Vlassov, Valentin
Zenkova, Marina
Dual miRNases for Triple Incision of miRNA Target: Design Concept and Catalytic Performance
title Dual miRNases for Triple Incision of miRNA Target: Design Concept and Catalytic Performance
title_full Dual miRNases for Triple Incision of miRNA Target: Design Concept and Catalytic Performance
title_fullStr Dual miRNases for Triple Incision of miRNA Target: Design Concept and Catalytic Performance
title_full_unstemmed Dual miRNases for Triple Incision of miRNA Target: Design Concept and Catalytic Performance
title_short Dual miRNases for Triple Incision of miRNA Target: Design Concept and Catalytic Performance
title_sort dual mirnases for triple incision of mirna target: design concept and catalytic performance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287882/
https://www.ncbi.nlm.nih.gov/pubmed/32466298
http://dx.doi.org/10.3390/molecules25102459
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