A massively parallel screening platform for converting aptamers into molecular switches

Alex M. Yoshikawa, Alexandra E. Rangel, Liwei Zheng, Leighton Wan, Linus A. Hein, Amani A. Hariri, Michael Eisenstein and H. Tom Soh ()
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Alex M. Yoshikawa: Stanford University
Alexandra E. Rangel: Stanford University
Liwei Zheng: Stanford University
Leighton Wan: Stanford University
Linus A. Hein: Stanford University
Amani A. Hariri: Stanford University
Michael Eisenstein: Stanford University
H. Tom Soh: Stanford University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Aptamer-based molecular switches that undergo a binding-induced conformational change have proven valuable for a wide range of applications, such as imaging metabolites in cells, targeted drug delivery, and real-time detection of biomolecules. Since conventional aptamer selection methods do not typically produce aptamers with inherent structure-switching functionality, the aptamers must be converted to molecular switches in a post-selection process. Efforts to engineer such aptamer switches often use rational design approaches based on in silico secondary structure predictions. Unfortunately, existing software cannot accurately model three-dimensional oligonucleotide structures or non-canonical base-pairing, limiting the ability to identify appropriate sequence elements for targeted modification. Here, we describe a massively parallel screening-based strategy that enables the conversion of virtually any aptamer into a molecular switch without requiring any prior knowledge of aptamer structure. Using this approach, we generate multiple switches from a previously published ATP aptamer as well as a newly-selected boronic acid base-modified aptamer for glucose, which respectively undergo signal-on and signal-off switching upon binding their molecular targets with second-scale kinetics. Notably, our glucose-responsive switch achieves ~30-fold greater sensitivity than a previously-reported natural DNA-based switch. We believe our approach could offer a generalizable strategy for producing target-specific switches from a wide range of aptamers.

Date: 2023
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DOI: 10.1038/s41467-023-38105-4

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