Identifying the preferred RNA motifs and chemotypes that interact by probing millions of combinations

Tran, Tuan Anh; Disney, Matthew D.

doi:10.1038/ncomms2119

Cited by 75 publications

(87 citation statements)

References 59 publications

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“…Furthermore, hairpin loops in general represent attractive targets for recognition by small molecules. In support of this notion, Tran and Disney have recently concluded from a multidimensional screening analysis that hairpin loops represent a preferred RNA motif space for binding small molecules (Tran and Disney 2012). Nevertheless, few sequence-specific small molecule ligands are known for RNA hairpin loops (Thomas and Hergenrother 2008).…”

Section: Discussionmentioning

confidence: 91%

Association of a peptoid ligand with the apical loop of pri-miR-21 inhibits cleavage by Drosha

Diaz

Chirayil

et al. 2014

RNA

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We have found a small molecule that specifically inhibits cleavage of a precursor to the oncogenic miRNA, miR-21, by the microprocessor complex of Drosha and DGCR8. We identified novel ligands for the apical loop of this precursor from a screen of 14,024 N-substituted oligoglycines (peptoids) in a microarray format. Eight distinct compounds with specific affinity were obtained, three having affinities for the targeted loop in the low micromolar range and greater than 15-fold discrimination against a closely related hairpin. One of these compounds completely inhibits microprocessor cleavage of a miR-21 primary transcript at concentrations at which cleavage of another miRNA primary transcript, pri-miR-16, is little affected. The apical loop of pri-miR-21, placed in the context of pri-miR-16, is sufficient for inhibition of microprocessor cleavage by the peptoid. This compound also inhibits cleavage of pri-miR-21 containing the pri-miR-16 apical loop, suggesting an additional site of association within pri-miR-21. The reported peptoid is the first example of a small molecule that inhibits microprocessor cleavage by binding to the apical loop of a pri-miRNA.

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Section: Discussionmentioning

confidence: 91%

Association of a peptoid ligand with the apical loop of pri-miR-21 inhibits cleavage by Drosha

Diaz

Chirayil

et al. 2014

RNA

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“…In addition to the chemotypes mentioned above, a previous study identified that 2-phenyl indole, 2-phenyl benzimidazole, and pyridinium chemotypes are privileged for binding RNA. (33) As more privileged scaffolds are identified, they can be used to refine current small molecule screening decks to create RNA-focused small molecule libraries.…”

Section: Resultsmentioning

confidence: 99%

Inforna 2.0: A Platform for the Sequence-Based Design of Small Molecules Targeting Structured RNAs

et al. 2016

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The development of small molecules that target RNA is challenging yet, if successful, could advance the development of chemical probes to study RNA function or precision therapeutics to treat RNA-mediated disease. Previously, we described Inforna, an approach that can mine motifs (secondary structures) within target RNAs, which is deduced from the RNA sequence, and compare them to a database of known RNA motif–small molecule binding partners. Output generated by Inforna includes the motif found in both the database and the desired RNA target, lead small molecules for that target, and other related meta-data. Lead small molecules can then be tested for binding and affecting cellular (dys)function. Herein, we describe Inforna 2.0, which incorporates all known RNA motif–small molecule binding partners reported in the scientific literature, a chemical similarity searching feature, and an improved user interface and is freely available via an online web server. By incorporation of interactions identified by other laboratories, the database has been doubled, containing 1936 RNA motif–small molecule interactions, including 244 unique small molecules and 1331 motifs. Interestingly, chemotype analysis of the compounds that bind RNA in the database reveals features in small molecule chemotypes that are privileged for binding. Further, this updated database expanded the number of cellular RNAs to which lead compounds can be identified.

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“…1d,f). As the binding sensitivity of aptamers towards chemicals, as well as the activation ratio of a riboswitch module, can be customized during the riboselector construction process 15,[26][27][28] , the selection cutoff levels could be further modulated according to the physiological conditions of the target strain.…”

Section: Resultsmentioning

confidence: 99%

Synthetic RNA devices to expedite the evolution of metabolite-producing microbes

et al. 2013

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An extension of directed evolution strategies to genome-wide variations increases the chance of obtaining metabolite-overproducing microbes. However, a general high-throughput screening platform for selecting improved strains remains out of reach. Here, to expedite the evolution of metabolite-producing microbes, we utilize synthetic RNA devices comprising a riboswitch and a selection module that specifically sense inconspicuous metabolites. Using L-lysine-producing Escherichia coli as a model system, we demonstrated that this RNA device could enrich pathway-optimized strains to up to 75% of the total population after four rounds of enrichment cycles. Furthermore, the potential applicability of this device was examined by successfully extending its application to the case of L-tryptophan. When used in conjunction with combinatorial mutagenesis for metabolite overproduction, our synthetic RNA device should facilitate strain improvement.

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Identifying the preferred RNA motifs and chemotypes that interact by probing millions of combinations

Cited by 75 publications

References 59 publications

Association of a peptoid ligand with the apical loop of pri-miR-21 inhibits cleavage by Drosha

Association of a peptoid ligand with the apical loop of pri-miR-21 inhibits cleavage by Drosha

Inforna 2.0: A Platform for the Sequence-Based Design of Small Molecules Targeting Structured RNAs

Synthetic RNA devices to expedite the evolution of metabolite-producing microbes

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