Engineering supramolecular dynamics of self-assembly and turnover of oncogenic microRNAs to drive their synergistic destruction in tumor models.

Autor: Chiglintseva D; Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentiev Avenue, 630090, Novosibirsk, Russia., Clarke DJ; School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK., Sen'kova A; Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentiev Avenue, 630090, Novosibirsk, Russia., Heyman T; School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK., Miroshnichenko S; Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentiev Avenue, 630090, Novosibirsk, Russia., Shan F; School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK., Vlassov V; Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentiev Avenue, 630090, Novosibirsk, Russia., Zenkova M; Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentiev Avenue, 630090, Novosibirsk, Russia., Patutina O; Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentiev Avenue, 630090, Novosibirsk, Russia. Electronic address: patutina@niboch.nsc.ru., Bichenkova E; 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.
Jazyk: angličtina
Zdroj: Biomaterials [Biomaterials] 2024 Sep; Vol. 309, pp. 122604. Date of Electronic Publication: 2024 May 06.
DOI: 10.1016/j.biomaterials.2024.122604
Abstrakt: Rationally-engineered functional biomaterials offer the opportunity to interface with complex biology in a predictive, precise, yet dynamic way to reprogram their behaviour and correct shortcomings. Success here may lead to a desired therapeutic effect against life-threatening diseases, such as cancer. Here, we engineered "Crab"-like artificial ribonucleases through coupling of peptide and nucleic acid building blocks, capable of operating alongside and synergistically with intracellular enzymes (RNase H and AGO2) for potent destruction of oncogenic microRNAs. "Crab"-like configuration of two catalytic peptides ("pincers") flanking the recognition oligonucleotide was instrumental here in providing increased catalytic turnover, leading to ≈30-fold decrease in miRNA half-life as compared with that for "single-pincer" conjugates. Dynamic modeling of miRNA cleavage illustrated how such design enabled "Crabs" to drive catalytic turnover through simultaneous attacks at different locations of the RNA-DNA heteroduplex, presumably by producing smaller cleavage products and by providing toeholds for competitive displacement by intact miRNA strands. miRNA cleavage at the 5'-site, spreading further into double-stranded region, likely provided a synergy for RNase H1 through demolition of its loading region, thus facilitating enzyme turnover. Such synergy was critical for sustaining persistent disposal of continually-emerging oncogenic miRNAs. A single exposure to the best structural variant (Crab-p-21) prior to transplantation into mice suppressed their malignant properties and reduced primary tumor volume (by 85 %) in MCF-7 murine xenograft models.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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