2. Academic Validation
  3. Selective small-molecule inhibition of an RNA structural element

Selective small-molecule inhibition of an RNA structural element

  • Nature. 2015 Oct 29;526(7575):672-7. doi: 10.1038/nature15542.
John A Howe 1,  Hao Wang 1,  Thierry O Fischmann 1,  Carl J Balibar 1,  Li Xiao 1,  Andrew M Galgoci 1,  Juliana C Malinverni 1,  Todd Mayhood 1,  Artjohn Villafania 1,  Ali Nahvi 2,  Nicholas Murgolo 1,  Christopher M Barbieri 1,  Paul A Mann 1,  Donna Carr 1,  Ellen Xia 1,  Paul Zuck 3,  Dan Riley 3,  Ronald E Painter 1,  Scott S Walker 1,  Brad Sherborne 1,  Reynalda de Jesus 1,  Weidong Pan 1,  Michael A Plotkin 1,  Jin Wu 1,  Diane Rindgen 1,  John Cummings 1,  Charles G Garlisi 1,  Rumin Zhang 1,  Payal R Sheth 1,  Charles J Gill 1,  Haifeng Tang 1,  Terry Roemer 1
Affiliations

Affiliations

  • 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.
PMID: 26416753 DOI: 10.1038/nature15542
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.

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