Tertiary RNA Folding-Targeted Drug Screening Strategy Using a Protein Nanopore

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Bacterial riboswitch RNAs are attractive targets for novel antibiotics against antibiotic-resistant superbacteria. Their binding to cognate metabolites is essential for the regulation of bacterial gene expression. Despite the importance of RNAs as therapeutic targets, the development of RNA-targeted, small-molecule drugs is limited by current biophysical methods. Here, we monitored the specific interaction between the adenine-sensing riboswitch aptamer domain (ARS) and adenine at the single-molecule level using alpha-hemolysin (alpha HL) nanopores. During adenine-induced tertiary folding, adenine-bound ARS intermediates exhibited characteristic nanopore events, including a two-level ionic current blockade and a similar to 5.6-fold longer dwell time than that of free RNA. In a proof-of-concept experiment, tertiary RNA folding-targeted drug screening was performed using a protein nanopore, which resulted in the discovery of three new ARS-targeting hit compounds from a natural compound library. Taken together, these results reveal that alpha HL nanopores are a valuable platform for ultrasensitive, label-free, and single-molecule-based drug screening against therapeutic RNA targets.
Publisher
AMER CHEMICAL SOC
Issue Date
2021-02
Language
English
Article Type
Article
Citation

ANALYTICAL CHEMISTRY, v.93, no.5, pp.2811 - 2819

ISSN
0003-2700
DOI
10.1021/acs.analchem.0c03941
URI
http://hdl.handle.net/10203/281586
Appears in Collection
BiS-Journal Papers(저널논문)
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