Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells

Childs‐Disney, Jessica L.; Disney, Matthew D.

doi:10.1146/annurev-pharmtox-010715-103910

Cited by 61 publications

(45 citation statements)

References 96 publications

(111 reference statements)

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“…M l RA‐19a is not only the first l ‐aptamer to be evolved by using modified nucleotides during the in vitro selection process but also the first modified aptamer (of any type) to be selected against a structured RNA target. This approach opens a route to precise targeting of a wide range of structured RNAs, thus addressing a long‐standing challenge in RNA biochemistry and drug discovery . Furthermore, our results suggested that l ‐aptamers, like their native counterparts, benefit from an expanded chemical repertoire.…”

Section: Figurementioning

confidence: 74%

“…This approach opens ar oute to precise targeting of aw ide range of structured RNAs, thusa ddressing al ong-standingc hallenge in RNA biochemistry and drug discovery. [14] Furthermore,o ur results suggested that l-aptamers, like their native counterparts, benefitf rom an expandedc hemical repertoire. In the future,i t will be important to screen additional modifiedn ucleotides during the in vitro selection process in order to identify those functional groups most apt for RNA binding.…”

mentioning

confidence: 98%

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An l‐RNA Aptamer with Expanded Chemical Functionality that Inhibits MicroRNA Biogenesis

Kabza

Sczepanski

2017

ChemBioChem

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To facilitate isolation of l-aptamers with novel RNA-binding properties, we employed a cationic nucleotide, 5-aminoallyluridine, during the mirror image in vitro selection process. Through this effort, we identified a modified l-RNA aptamer (MlRA) capable of binding oncogenic precursor microRNA 19a (pre-miR-19a) with exceptional affinity, and we showed that cationic modification is absolutely critical for binding. Furthermore, formation of the MlRA-pre-miR-19a complex inhibited Dicer-mediated cleavage of the pre-miR, thus blocking formation of the mature functional microRNA. The MlRA reported here not only represents the first l-aptamer to be evolved by using modified nucleotides but also the first modified aptamer (of any type) to be selected against a structured RNA target. Our results demonstrate that functionalized l-aptamers, which are intrinsically nuclease-resistant, provide an attractive approach for developing robust RNA-binding reagents.

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Section: Figurementioning

confidence: 74%

mentioning

confidence: 98%

An l‐RNA Aptamer with Expanded Chemical Functionality that Inhibits MicroRNA Biogenesis

Kabza

Sczepanski

2017

ChemBioChem

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“…Notably, small molecules have also been proposed to target disease-causing nucleic acid targets and modulate their function 19 . The advantage of this approach is that it would apply the advantages of small molecules to DNA and RNA “receptors”.…”

Section: Targeting Mrna: Principles and Lessons Learnedmentioning

confidence: 99%

Non-coding RNAs as drug targets

Matsui

Corey

2016

Nat Rev Drug Discov

839

622

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Most of the human genome encodes RNA that does not code for protein. These noncoding RNAs (ncRNAs) may affect normal gene expression and disease progression, making them a new class of targets for drug discovery. Because their mechanisms of action are often novel, developing drugs targeting ncRNAs will involve equally novel challenges. However, many potential problems may already have been solved during development of technologies to target mRNA. Here, we will discuss the growing field of ncRNA – including microRNA, intronic RNA, repetitive RNA and long non-coding RNA - and assess the potential and challenges in their therapeutic exploitation.

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“…32-35 Approximating loop stability and probability from sequence is a key to accurate prediction of secondary structure. 6, 36, 37 Moreover, small loops provide benchmarks for testing computational approaches for predicting RNA thermodynamic stability and 3D structure.…”

Section: Introductionmentioning

confidence: 99%

Surprising Sequence Effects on GU Closure of Symmetric 2 × 2 Nucleotide RNA Internal Loops

et al. 2018

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GU base pairs are important RNA structural motifs and often close loops. Accurate prediction of RNA structures relies upon understanding the interactions determining structure. The thermodynamics of some two-by-two nucleotide internal loops closed by GU pairs are not well understood. Here, several self-complementary oligonucleotide sequences expected to form duplexes with two-by-two nucleotide internal loops closed by GU pairs were investigated. Surprisingly, NMR revealed that many of the sequences exist in equilibrium between hairpin and duplex conformations. This equilibrium is not observed with loops closed by Watson-Crick pairs. To measure the thermodynamics of some two-by-two nucleotide internal loops closed by GU pairs, non-self-complementary sequences were designed that preclude formation of hairpins. The measured thermodynamics indicate that some internal loops closed by GU pairs are unusually unstable. This instability accounts for the observed equilibria between duplex and hairpin conformations. Moreover, it suggests that future three dimensional structures of loops closed by GU pairs may reveal interactions that unexpectedly destabilize folding.

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Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells

Cited by 61 publications

References 96 publications

An l‐RNA Aptamer with Expanded Chemical Functionality that Inhibits MicroRNA Biogenesis

An l‐RNA Aptamer with Expanded Chemical Functionality that Inhibits MicroRNA Biogenesis

Non-coding RNAs as drug targets

Surprising Sequence Effects on GU Closure of Symmetric 2 × 2 Nucleotide RNA Internal Loops

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