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Studying the selectivity of a targeted small molecule degrading a hypoxia-associated non-coding RNA

ABSTRACT: Studying the selectivity of a targeted small molecule degrading a hypoxia-associated non-coding RNA

PROVIDER: PRJNA530777 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8844470_1.fastq.gz	Fastqsanger.gz
	SRR8844470_2.fastq.gz	Fastqsanger.gz
	SRR8844480_1.fastq.gz	Fastqsanger.gz
	SRR8844480_2.fastq.gz	Fastqsanger.gz
	SRR8844461_1.fastq.gz	Fastqsanger.gz

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Studying the selectivity of a targeted small molecule degrading a hypoxia-associated non-coding RNA

Project description:Small molecule targeted recruitment of nucleases to RNA is a powerful method to affect RNA biology. Inforna, a sequence-based design approach to target RNA, enables the design of small molecules that bind and cleave RNA in a selective and substoichiometric manner. Herein, we investigate the ability of RNA targeted degradation to improve the selectivity of small molecules targeting RNA. The microRNA-210 hairpin precursor (pre-miR-210) is overexpressed in hypoxic cancers. Previously, a small molecule (Targapremir-210, TGP-210) targeted this RNA in cells, but with only a 5-fold window for DNA binding. Appendage of a nuclease recruitment module onto TGP-210 locally recruited ribonuclease L onto pre-miR-210, triggering its degradation. The chimera has enhanced selectivity compared to TGP-210 with nanomolar binding to the pre-miR-210, but no DNA binding, and is broadly selective for affecting RNA function in cells. Importantly, it cleaved pre-miR-210 substoichiometrically and induced apoptosis in breast cancer cells.

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Targeted Degradation of a Hypoxia-Associated Non-coding RNA Enhances the Selectivity of a Small Molecule Interacting with RNA.

Project description:Small-molecule targeted recruitment of nucleases to RNA is a powerful method to affect RNA biology. Inforna, a sequence-based design approach to target RNA, enables the design of small molecules that bind to and cleave RNA in a selective and substoichiometric manner. Here, we investigate the ability of RNA-targeted degradation to improve the selectivity of small molecules targeting RNA. The microRNA-210 hairpin precursor (pre-miR-210) is overexpressed in hypoxic cancers. Previously, a small molecule (Targapremir-210 [TGP-210]) targeted this RNA in cells, but with a 5-fold window for DNA binding. Appendage of a nuclease recruitment module onto TGP-210 locally recruited ribonuclease L onto pre-miR-210, triggering its degradation. The chimera has enhanced selectivity compared with TGP-210 with nanomolar binding to the pre-miR-210, but no DNA binding, and is broadly selective for affecting RNA function in cells. Importantly, it cleaved pre-miR-210 substoichiometrically and induced apoptosis in breast cancer cells.

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