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Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer

As the area of small molecules interacting with RNA advances, general routes to provide bioactive compounds are needed as ligands can bind RNA avidly to sites that will not affect function. Small-molecule targeted RNA degradation will thus provide a general route to affect RNA biology. A non–oligonu...

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Autores principales: Costales, Matthew G., Aikawa, Haruo, Li, Yue, Childs-Disney, Jessica L., Abegg, Daniel, Hoch, Dominic G., Pradeep Velagapudi, Sai, Nakai, Yoshio, Khan, Tanya, Wang, Kye Won, Yildirim, Ilyas, Adibekian, Alexander, Wang, Eric T., Disney, Matthew D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007575/
https://www.ncbi.nlm.nih.gov/pubmed/31964809
http://dx.doi.org/10.1073/pnas.1914286117
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author Costales, Matthew G.
Aikawa, Haruo
Li, Yue
Childs-Disney, Jessica L.
Abegg, Daniel
Hoch, Dominic G.
Pradeep Velagapudi, Sai
Nakai, Yoshio
Khan, Tanya
Wang, Kye Won
Yildirim, Ilyas
Adibekian, Alexander
Wang, Eric T.
Disney, Matthew D.
author_facet Costales, Matthew G.
Aikawa, Haruo
Li, Yue
Childs-Disney, Jessica L.
Abegg, Daniel
Hoch, Dominic G.
Pradeep Velagapudi, Sai
Nakai, Yoshio
Khan, Tanya
Wang, Kye Won
Yildirim, Ilyas
Adibekian, Alexander
Wang, Eric T.
Disney, Matthew D.
author_sort Costales, Matthew G.
collection PubMed
description As the area of small molecules interacting with RNA advances, general routes to provide bioactive compounds are needed as ligands can bind RNA avidly to sites that will not affect function. Small-molecule targeted RNA degradation will thus provide a general route to affect RNA biology. A non–oligonucleotide-containing compound was designed from sequence to target the precursor to oncogenic microRNA-21 (pre–miR-21) for enzymatic destruction with selectivity that can exceed that for protein-targeted medicines. The compound specifically binds the target and contains a heterocycle that recruits and activates a ribonuclease to pre–miR-21 to substoichiometrically effect its cleavage and subsequently impede metastasis of breast cancer to lung in a mouse model. Transcriptomic and proteomic analyses demonstrate that the compound is potent and selective, specifically modulating oncogenic pathways. Thus, small molecules can be designed from sequence to have all of the functional repertoire of oligonucleotides, including inducing enzymatic degradation, and to selectively and potently modulate RNA function in vivo.
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spelling pubmed-70075752020-02-18 Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer Costales, Matthew G. Aikawa, Haruo Li, Yue Childs-Disney, Jessica L. Abegg, Daniel Hoch, Dominic G. Pradeep Velagapudi, Sai Nakai, Yoshio Khan, Tanya Wang, Kye Won Yildirim, Ilyas Adibekian, Alexander Wang, Eric T. Disney, Matthew D. Proc Natl Acad Sci U S A Biological Sciences As the area of small molecules interacting with RNA advances, general routes to provide bioactive compounds are needed as ligands can bind RNA avidly to sites that will not affect function. Small-molecule targeted RNA degradation will thus provide a general route to affect RNA biology. A non–oligonucleotide-containing compound was designed from sequence to target the precursor to oncogenic microRNA-21 (pre–miR-21) for enzymatic destruction with selectivity that can exceed that for protein-targeted medicines. The compound specifically binds the target and contains a heterocycle that recruits and activates a ribonuclease to pre–miR-21 to substoichiometrically effect its cleavage and subsequently impede metastasis of breast cancer to lung in a mouse model. Transcriptomic and proteomic analyses demonstrate that the compound is potent and selective, specifically modulating oncogenic pathways. Thus, small molecules can be designed from sequence to have all of the functional repertoire of oligonucleotides, including inducing enzymatic degradation, and to selectively and potently modulate RNA function in vivo. National Academy of Sciences 2020-02-04 2020-01-21 /pmc/articles/PMC7007575/ /pubmed/31964809 http://dx.doi.org/10.1073/pnas.1914286117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Costales, Matthew G.
Aikawa, Haruo
Li, Yue
Childs-Disney, Jessica L.
Abegg, Daniel
Hoch, Dominic G.
Pradeep Velagapudi, Sai
Nakai, Yoshio
Khan, Tanya
Wang, Kye Won
Yildirim, Ilyas
Adibekian, Alexander
Wang, Eric T.
Disney, Matthew D.
Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer
title Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer
title_full Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer
title_fullStr Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer
title_full_unstemmed Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer
title_short Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer
title_sort small-molecule targeted recruitment of a nuclease to cleave an oncogenic rna in a mouse model of metastatic cancer
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007575/
https://www.ncbi.nlm.nih.gov/pubmed/31964809
http://dx.doi.org/10.1073/pnas.1914286117
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