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Nature. 2015 Oct 29;526(7575):672-7. doi: 10.1038/nature15542. Epub 2015 Sep 30.

Selective small-molecule inhibition of an RNA structural element.

Author information

1
Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
2
Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
3
Merck Research Laboratories, North Wales, Pennsylvania 19454, USA.

Abstract

Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.

PMID:
26416753
DOI:
10.1038/nature15542
[Indexed for MEDLINE]

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