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

Autor:	Costales MG; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458., Aikawa H; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458., Li Y; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458., Childs-Disney JL; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458., Abegg D; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458., Hoch DG; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458., Pradeep Velagapudi S; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458., Nakai Y; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458., Khan T; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458., Wang KW; Department of Chemistry and Biochemistry, Florida Atlantic University, Jupiter, FL 33458., Yildirim I; Department of Chemistry and Biochemistry, Florida Atlantic University, Jupiter, FL 33458., Adibekian A; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458., Wang ET; Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, FL 32610., Disney MD; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458; DISNEY@scripps.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Feb 04; Vol. 117 (5), pp. 2406-2411. Date of Electronic Publication: 2020 Jan 21.
DOI:	10.1073/pnas.1914286117
Abstrakt:	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. Competing Interests: Competing interest statement: M.D.D. is a founder of Expansion Therapeutics and M.D.D. and E.T.W. are consultants for Expansion Therapeutics. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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