Tertiary RNA folding-targeted drug screening strategy using a protein nanopore

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Title
Tertiary RNA folding-targeted drug screening strategy using a protein nanopore
Author(s)
Dong-Hwa Lee; Sohee Oh; Kyungeun Lim; B Lee; G S Yi; Y R Kim; K B Kim; C K Lee; Seung-Wook ChiMi-Kyung Lee
Bibliographic Citation
Analytical Chemistry, vol. 93, no. 5, pp. 2811-2819
Publication Year
2021
Abstract
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 α-hemolysin (αHL) nanopores. During adenine-induced tertiary folding, adenine-bound ARS intermediates exhibited characteristic nanopore events, including a two-level ionic current blockade and a ∼ 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 αHL nanopores are a valuable platform for ultrasensitive, label-free, and single-molecule-based drug screening against therapeutic RNA targets.
ISSN
0003-2700
Publisher
Amer Chem Soc
DOI
http://dx.doi.org/10.1021/acs.analchem.0c03941
Type
Article
Appears in Collections:
Division of Biomedical Research > 1. Journal Articles
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
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