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Selective small-molecule inhibition of an RNA structural element.

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.
Nature; 526(7575): 672-7, 2015 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-26416753
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.
Selo DaSilva