Selective small-molecule inhibition of an RNA structural element

John A. Howe, Hao Wang, Thierry O. Fischmann, Carl J. Balibar, Li Xiao, Andrew M. Galgoci, Juliana C. Malinverni, Todd Mayhood, Artjohn Villafania, Ali Nahvi, Nicholas Murgolo, Christopher M. Barbieri, Paul A. Mann, Donna Carr, Ellen Xia, Paul Zuck, Dan Riley, Ronald E. Painter, Scott S. Walker, Brad Sherborne, Reynalda de Jesus, Weidong Pan, Michael A. Plotkin, Jin Wu, Diane Rindgen, John Cummings, Charles G. Garlisi, Rumin Zhang, Payal R. Sheth, Charles J. Gill, Haifeng Tang and Terry Roemer ()
Additional contact information
John A. Howe: Merck Research Laboratories
Hao Wang: Merck Research Laboratories
Thierry O. Fischmann: Merck Research Laboratories
Carl J. Balibar: Merck Research Laboratories
Li Xiao: Merck Research Laboratories
Andrew M. Galgoci: Merck Research Laboratories
Juliana C. Malinverni: Merck Research Laboratories
Todd Mayhood: Merck Research Laboratories
Artjohn Villafania: Merck Research Laboratories
Ali Nahvi: Merck Research Laboratories
Nicholas Murgolo: Merck Research Laboratories
Christopher M. Barbieri: Merck Research Laboratories
Paul A. Mann: Merck Research Laboratories
Donna Carr: Merck Research Laboratories
Ellen Xia: Merck Research Laboratories
Paul Zuck: Merck Research Laboratories
Dan Riley: Merck Research Laboratories
Ronald E. Painter: Merck Research Laboratories
Scott S. Walker: Merck Research Laboratories
Brad Sherborne: Merck Research Laboratories
Reynalda de Jesus: Merck Research Laboratories
Weidong Pan: Merck Research Laboratories
Michael A. Plotkin: Merck Research Laboratories
Jin Wu: Merck Research Laboratories
Diane Rindgen: Merck Research Laboratories
John Cummings: Merck Research Laboratories
Charles G. Garlisi: Merck Research Laboratories
Rumin Zhang: Merck Research Laboratories
Payal R. Sheth: Merck Research Laboratories
Charles J. Gill: Merck Research Laboratories
Haifeng Tang: Merck Research Laboratories
Terry Roemer: Merck Research Laboratories

Nature, 2015, vol. 526, issue 7575, 672-677

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature15542

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