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Title: Selective small-molecule inhibition of an RNA structural element

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.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1377918
Resource Type:
Journal Article
Journal Name:
Nature (London)
Additional Journal Information:
Journal Volume: 526; Journal Issue: 7575; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Howe, John A., Wang, Hao, Fischmann, Thierry O., Balibar, Carl J., Xiao, Li, Galgoci, Andrew M., Malinverni, Juliana C., Mayhood, Todd, Villafania, Artjohn, Nahvi, Ali, Murgolo, Nicholas, Barbieri, Christopher M., Mann, Paul A., Carr, Donna, Xia, Ellen, Zuck, Paul, Riley, Dan, Painter, Ronald E., Walker, Scott S., Sherborne, Brad, de Jesus, Reynalda, Pan, Weidong, Plotkin, Michael A., Wu, Jin, Rindgen, Diane, Cummings, John, Garlisi, Charles G., Zhang, Rumin, Sheth, Payal R., Gill, Charles J., Tang, Haifeng, and Roemer, Terry. Selective small-molecule inhibition of an RNA structural element. United States: N. p., 2015. Web. doi:10.1038/nature15542.
Howe, John A., Wang, Hao, Fischmann, Thierry O., Balibar, Carl J., Xiao, Li, Galgoci, Andrew M., Malinverni, Juliana C., Mayhood, Todd, Villafania, Artjohn, Nahvi, Ali, Murgolo, Nicholas, Barbieri, Christopher M., Mann, Paul A., Carr, Donna, Xia, Ellen, Zuck, Paul, Riley, Dan, Painter, Ronald E., Walker, Scott S., Sherborne, Brad, de Jesus, Reynalda, Pan, Weidong, Plotkin, Michael A., Wu, Jin, Rindgen, Diane, Cummings, John, Garlisi, Charles G., Zhang, Rumin, Sheth, Payal R., Gill, Charles J., Tang, Haifeng, & Roemer, Terry. Selective small-molecule inhibition of an RNA structural element. United States. doi:10.1038/nature15542.
Howe, John A., Wang, Hao, Fischmann, Thierry O., Balibar, Carl J., Xiao, Li, Galgoci, Andrew M., Malinverni, Juliana C., Mayhood, Todd, Villafania, Artjohn, Nahvi, Ali, Murgolo, Nicholas, Barbieri, Christopher M., Mann, Paul A., Carr, Donna, Xia, Ellen, Zuck, Paul, Riley, Dan, Painter, Ronald E., Walker, Scott S., Sherborne, Brad, de Jesus, Reynalda, Pan, Weidong, Plotkin, Michael A., Wu, Jin, Rindgen, Diane, Cummings, John, Garlisi, Charles G., Zhang, Rumin, Sheth, Payal R., Gill, Charles J., Tang, Haifeng, and Roemer, Terry. Wed . "Selective small-molecule inhibition of an RNA structural element". United States. doi:10.1038/nature15542.
@article{osti_1377918,
title = {Selective small-molecule inhibition of an RNA structural element},
author = {Howe, John A. and Wang, Hao and Fischmann, Thierry O. and Balibar, Carl J. and Xiao, Li and Galgoci, Andrew M. and Malinverni, Juliana C. and Mayhood, Todd and Villafania, Artjohn and Nahvi, Ali and Murgolo, Nicholas and Barbieri, Christopher M. and Mann, Paul A. and Carr, Donna and Xia, Ellen and Zuck, Paul and Riley, Dan and Painter, Ronald E. and Walker, Scott S. and Sherborne, Brad and de Jesus, Reynalda and Pan, Weidong and Plotkin, Michael A. and Wu, Jin and Rindgen, Diane and Cummings, John and Garlisi, Charles G. and Zhang, Rumin and Sheth, Payal R. and Gill, Charles J. and Tang, Haifeng and Roemer, Terry},
abstractNote = {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.},
doi = {10.1038/nature15542},
journal = {Nature (London)},
issn = {0028-0836},
number = 7575,
volume = 526,
place = {United States},
year = {2015},
month = {9}
}