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.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Howe
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Thierry O
authors.initials: TO
authors.lastname: Fischmann
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Balibar
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Galgoci
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Juliana C
authors.initials: JC
authors.lastname: Malinverni
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Mayhood
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Artjohn
authors.initials: A
authors.lastname: Villafania
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Nahvi
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Murgolo
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Barbieri
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Mann
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Carr
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Xia
authors.affiliation: Merck Research Laboratories, North Wales, Pennsylvania 19454, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Zuck
authors.affiliation: Merck Research Laboratories, North Wales, Pennsylvania 19454, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Riley
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Painter
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Walker
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Sherborne
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Reynalda
authors.initials: R
authors.lastname: de Jesus
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Pan
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Plotkin
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Rindgen
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: John
authors.initials: J
authors.lastname: Cummings
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Garlisi
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Rumin
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Payal R
authors.initials: PR
authors.lastname: Sheth
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Gill
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Tang
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Roemer
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000737:chemistry; D001419:Bacteria / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D001483:Base Sequence; D018360:Crystallography, X-Ray; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000235:genetics; D005260:Female; D005486:Flavin Mononucleotide / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics; D019751:Intramolecular Transferases / Q000235:genetics; D008024:Ligands; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011743:Pyrimidines / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D012329:RNA, Bacterial / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D015203:Reproducibility of Results; D012256:Riboflavin / Q000096:biosynthesis; D058928:Riboswitch / Q000187:drug effects* / Q000235:genetics; D013379:Substrate Specificity
chemical_list: D052157:Aptamers, Nucleotide; D029968:Escherichia coli Proteins; D006360:Heat-Shock Proteins; D008024:Ligands; D011743:Pyrimidines; D012329:RNA, Bacterial; D058928:Riboswitch; C000602893:ribocil; C071147:ribB protein, E coli; D005486:Flavin Mononucleotide; D019751:Intramolecular Transferases; D012256:Riboflavin