Sensing the impact of environment on small molecule differentiation of RNA sequences

Eubanks, Christopher S.; Hargrove, Amanda E.

doi:10.1039/c7cc07157d

Cited by 16 publications

(18 citation statements)

References 37 publications

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“…Moreover, the applications of this method in the field of nucleic acids sensing are scarce and mainly limited to the recognition of specific sequences, in line with usual applications. [40][41][42] Herein, we describe the first fluorescence sensor array designed for secondary structure analysis of DNA samples. Our work aims at providing a proof-of-concept of the applicability of such an approach to the categorization of oligonucleotides based on their secondary structure instead of their specific identity.…”

Section: Introductionmentioning

confidence: 99%

Strength in Numbers: Development of a Fluorescence Sensor Array for Secondary Structures of DNA

Zuffo

Xie

Granzhan

2019

Chemistry A European J

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High-throughput assessment of secondary structures adopted by DNA oligonucleotides is currently hampered by the lack of suitable biophysical methods. Fluorescent sensors hold great potential in this respect; however, the moderate selectivity that they display for one DNA conformation over the others constitutes a major drawback to the development of accurate assays. Moreover, the use of single sensors impedes a comprehensive classification of the tested sequences. Herein, we propose to overcome these limitations through the development of a fluorescence sensor array constituted by easily accessible, commercial dyes. Multivariate analysis of the emission data matrix produced by the array allows to explore the conformational preferences of DNA sequences of interest, either by calculating the probability of group membership in the six predefined structural categories (three G-quadruplex groups, double-stranded, and two groups of single-stranded forms), or by revealing their particular structural features. The assay enables rapid screening of synthetic DNA oligonucleotides in a 96-well plate format.

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Section: Introductionmentioning

confidence: 99%

Strength in Numbers: Development of a Fluorescence Sensor Array for Secondary Structures of DNA

Zuffo

Xie

Granzhan

2019

Chemistry A European J

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“…While it is possible that these rules may be RNA class‐specific, identifying the importance of factors such as: (a) RNA abundance; (b) RNA localization; (c) the availability of functional sites for binding; (d) structural rigidity; and (e) the complexity of the RNA 3D and/or quaternary structures will be crucial as researchers pursue small molecule development for the underexplored RNA classes described above. Advances in methods that enable robust characterization of RNA 3D structure, dynamics and in‐cell interactions, as well as characterization of RNA–ligand interfaces, could accelerate our understanding of these principles (Baird, Inglese, & Ferre‐D'Amare, ; Eubanks, Forte, Kapral, & Hargrove, ; Eubanks & Hargrove, ; Feng et al, ; Lu, Gong, & Zhang, ; Smola, Rice, Busan, Siegfried, & Weeks, ).…”

Section: Discussionmentioning

confidence: 99%

Targeting RNA in mammalian systems with small molecules

2018

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The recognition of RNA functions beyond canonical protein synthesis has challenged the central dogma of molecular biology. Indeed, RNA is now known to directly regulate many important cellular processes, including transcription, splicing, translation, and epigenetic modifications. The misregulation of these processes in disease has led to an appreciation of RNA as a therapeutic target. This potential was first recognized in bacteria and viruses, but discoveries of new RNA classes following the sequencing of the human genome have invigorated exploration of its disease-related functions in mammals. As stable structure formation is evolving as a hallmark of mammalian RNAs, the prospect of utilizing small molecules to specifically probe the function of RNA structural domains and their interactions is gaining increased recognition. To date, researchers have discovered bioactive small molecules that modulate phenotypes by binding to expanded repeats, microRNAs, G-quadruplex structures, and RNA splice sites in neurological disorders, cancers, and other diseases. The lessons learned from achieving these successes both call for additional studies and encourage exploration of the plethora of mammalian RNAs whose precise mechanisms of action remain to be elucidated. Efforts toward understanding fundamental principles of small molecule-RNA recognition combined with advances in methodology development should pave the way toward targeting emerging RNA classes such as long noncoding RNAs. Together, these endeavors can unlock the full potential of small molecule-based probing of RNA-regulated processes and enable us to discover new biology and underexplored avenues for therapeutic intervention in human disease. This article is categorized under: RNA Methods > RNA Analyses In Vitro and In Silico RNA Interactions with Proteins and Other Molecules > Small Molecule-RNA Interactions RNA in Disease and Development > RNA in Disease.

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“…It is well known that alternative or less-populated structures may exist in the dynamic ensemble of an RNA target of interest, and that environmental factors such as temperature and salt concentrations should be considered when assessing the accuracy of the predicted RNA structure. [35][36][37] In the future, we plan on incorporating features in which these factors can be controlled, in addition to predicting the likelihood of forming more complex structures such as G-quadruplexes. In casting a wide net with the RNA Structure Search and identifying all molecules that have been reported to bind a broad set of secondary structure motifs, the promise of RNA-targeting ligands will be a possibility for many therapeutically relevant RNA structures.…”

Section: Rna Structure Search Featurementioning

confidence: 99%

R-BIND 2.0: An Updated Database of Bioactive RNA-Targeting Small Molecules and Associated RNA Secondary Structures

Donlic

Swanson

Chiu

et al. 2022

Preprint

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Discoveries of RNA roles in cellular physiology and pathology are raising the need for new tools that modulate the structure and function of these biomolecules, and small molecules are proving useful. In 2017, we curated the RNA-targeted BIoactive ligaNd Database (R-BIND) and discovered distinguishing physicochemical properties of RNA-targeting ligands, leading us to propose the existence of an RNA-privileged chemical space. Biennial updates of the database and the establishment of a website platform (rbind.chem.duke.edu) have provided new insights and tools to design small molecules based on the analyzed physicochemical and spatial properties. In this report and R-BIND 2.0 update, we refined the curation approach and ligand classification system as well as conducted analyses of RNA structure elements for the first time to identify new targeting strategies. Specifically, we curated and analyzed RNA target structural motifs to determine properties of small molecules that may confer selectivity for distinct RNA secondary and tertiary structures. Additionally, we collected sequences of target structures and incorporated an RNA Structure Search algorithm into the website that outputs small molecules targeting similar motifs without a priori secondary structure knowledge. Cheminformatic analyses revealed that, despite the 50% increase in small molecule library size, the distinguishing properties of R-BIND ligands remained significantly different to that of proteins and are therefore still relevant to RNA-targeted probe discovery. Combined, we expect these novel insights and website features to enable rational design of RNA-targeted ligands and to serve as a resource and inspiration for a variety of scientists interested in RNA targeting.

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Sensing the impact of environment on small molecule differentiation of RNA sequences

Cited by 16 publications

References 37 publications

Strength in Numbers: Development of a Fluorescence Sensor Array for Secondary Structures of DNA

Strength in Numbers: Development of a Fluorescence Sensor Array for Secondary Structures of DNA

Targeting RNA in mammalian systems with small molecules

R-BIND 2.0: An Updated Database of Bioactive RNA-Targeting Small Molecules and Associated RNA Secondary Structures

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