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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7287882 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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