Publication Date:
2015-09-30
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- England -- Nature. 2015 Oct 29;526(7575):672-7. doi: 10.1038/nature15542. Epub 2015 Sep 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Merck Research Laboratories, Kenilworth, New Jersey 07033, USA. ; Merck Research Laboratories, West Point, Pennsylvania 19486, USA. ; Merck Research Laboratories, North Wales, Pennsylvania 19454, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26416753" target="_blank"〉PubMed〈/a〉
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
