RNA as a Drug Target

Ferner, Jan-Peter; Ferner, Elke Duchardt; Rinnenthal, Jörg; Buck, Janina; Wöhnert, Jens; Schwalbe, Harald

doi:10.1002/9783527644506.ch17

Cited by 2 publications

(4 citation statements)

References 10 publications

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“…This wide array of functions is partially enabled by RNA's intrinsic flexibility, which provides ready access to different conformations (9)(10)(11). As a direct result of structural studies that elucidate RNA conformations (12)(13)(14)(15), there has been increasing interest in pharmaceutical applications for functional RNA molecules (16)(17)(18)(19). Because of RNA's hierarchically organized structures, identifying the roles of individual RNA structural elements has been an effective lens for visualizing RNA folding pathways (20).…”

Section: Introductionmentioning

confidence: 99%

Conformations of an RNA Helix-Junction-Helix Construct Revealed by SAXS Refinement of MD Simulations

Chen

Lee

Elber

et al. 2019

Biophysical Journal

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RNA is involved in a broad range of biological processes that extend far beyond translation. Many of RNA's recently discovered functions rely on folding to a specific conformation or transitioning between conformations. The RNA structure contains rigid, short basepaired regions connected by more flexible linkers. Studies of model constructs such as small helix-junction-helix (HJH) motifs are useful in understanding how these elements work together to determine RNA conformation. Here, we reveal the full ensemble of solution structures assumed by a model RNA HJH. We apply small-angle x-ray scattering and an ensemble optimization method to selectively refine models generated by all-atom molecular dynamics simulations. The expectation of a broad distribution of helix orientations, at and above physiological ionic strength, is not met. Instead, this analysis shows that the HJH structures are dominated by two distinct conformations at moderate to high ionic strength. Atomic structures, selected from the molecular dynamics simulations, reveal strong base-base interactions in the junction that critically constrain the conformational space available to the HJH molecule and lead to a surprising re-extension at high salt. These results are corroborated by comparison with previous single-molecule fluorescence resonance energy transfer experiments on the same constructs.

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Section: Introductionmentioning

confidence: 99%

Conformations of an RNA Helix-Junction-Helix Construct Revealed by SAXS Refinement of MD Simulations

Chen

Lee

Elber

et al. 2019

Biophysical Journal

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“…Many regulatory RNA elements are emerging as new potential drug targets for treating a wide range of diseases 1-5 . For example, riboswitches are RNA-based gene regulatory elements in bacteria that form complex 3D structures, and are being targeted in the development of antibiotics 6-8 .…”

Section: Introductionmentioning

confidence: 99%

“…Many RNA hairpin structures, including bacterial 9,10 and retroviral elements 11-15 , human micro-RNAs 16 , various repeats 17,18 as well as more complex pseudoknots 19 are being targeted in the development of therapeutics against infectious diseases, diabetes, various genetic disorders, and cancer. There is growing interest in using experimental and computational high throughput screens (HTS) to identify small molecules that can target RNA 2-5 and that overcome delivery limitations inherent to large molecular weight RNA-based therapeutics such as antisense 20 and small interfering RNAs 21 .…”

Section: Introductionmentioning

confidence: 99%

“…Many regulatory RNA elements are emerging as new potential drug targets for treating a wide range of diseases. − For example, riboswitches are RNA-based gene regulatory elements in bacteria that form complex 3D structures and are being targeted in the development of antibiotics. − Many RNA hairpin structures, including bacterial , and retroviral elements, − human micro-RNAs, and various repeats , as well as more complex pseudoknots, are being targeted in the development of therapeutics against infectious diseases, diabetes, various genetic disorders, and cancer. There is growing interest in using experimental and computational high throughput screens (HTS) to identify small molecules that can target RNA − and that overcome delivery limitations inherent to large molecular weight RNA-based therapeutics such as antisense and small interfering RNAs …”

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confidence: 99%

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Influence of Dimethylsulfoxide on RNA Structure and Ligand Binding

et al. 2013

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Dimethyl sulfoxide (DMSO) is widely used as a cosolvent to solubilize hydrophobic compounds in RNA-ligand binding assays. Although it is known that high concentrations of DMSO (>75%) can significantly affect RNA structure and folding energetics, a thorough analysis of how lower concentrations (<10%) of DMSO typically used in binding assays affects RNA structure and ligand binding has not been undertaken. Here, we use NMR and 2-aminopurine fluorescence spectroscopy to examine how DMSO affects the structure, dynamics, and ligand binding properties of two flexible hairpin RNAs; the transactivation response element from HIV-1 and bacterial ribosomal A-site. In both cases, 5%-10% DMSO decreased stacking interactions and increased local disorder in non-canonical residues within bulges and loops and resulted in 0.3–4 fold reduction in the measured binding affinities for different small molecules, with the greatest reduction observed for an intercalating compound that binds RNA non-specifically. Our results suggest that by competing for hydrophobic interactions, DMSO can have a small but significant effect on RNA structure and ligand binding. These effects should be considered when developing ligand binding assays and high throughput screens.

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RNA as a Drug Target

Cited by 2 publications

References 10 publications

Conformations of an RNA Helix-Junction-Helix Construct Revealed by SAXS Refinement of MD Simulations

Conformations of an RNA Helix-Junction-Helix Construct Revealed by SAXS Refinement of MD Simulations

Influence of Dimethylsulfoxide on RNA Structure and Ligand Binding

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