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A massively parallel screening platform for converting aptamers into molecular switches

Author

Listed:
  • 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
    Stanford University)

  • H. Tom Soh

    (Stanford University
    Stanford University
    Chan Zuckerberg Biohub)

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.

Suggested Citation

  • Alex M. Yoshikawa & Alexandra E. Rangel & Liwei Zheng & Leighton Wan & Linus A. Hein & Amani A. Hariri & Michael Eisenstein & H. Tom Soh, 2023. "A massively parallel screening platform for converting aptamers into molecular switches," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38105-4
    DOI: 10.1038/s41467-023-38105-4
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    References listed on IDEAS

    as
    1. Ran Mo & Tianyue Jiang & Rocco DiSanto & Wanyi Tai & Zhen Gu, 2014. "ATP-triggered anticancer drug delivery," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    2. Deepak K. Prusty & Volker Adam & Reza M. Zadegan & Stephan Irsen & Michael Famulok, 2018. "Supramolecular aptamer nano-constructs for receptor-mediated targeting and light-triggered release of chemotherapeutics into cancer cells," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    3. Alex M. Yoshikawa & Alexandra Rangel & Trevor Feagin & Elizabeth M. Chun & Leighton Wan & Anping Li & Leonhard Moeckl & Diana Wu & Michael Eisenstein & Sharon Pitteri & H. Tom Soh, 2021. "Discovery of indole-modified aptamers for highly specific recognition of protein glycoforms," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    4. Brandon D. Wilson & Amani A. Hariri & Ian A. P. Thompson & Michael Eisenstein & H. Tom Soh, 2019. "Independent control of the thermodynamic and kinetic properties of aptamer switches," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
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