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Rapid discovery and evolution of nanosensors containing fluorogenic amino acids

Author

Listed:
  • Erkin Kuru

    (Harvard Medical School
    Harvard University)

  • Jonathan Rittichier

    (Harvard Medical School
    Harvard University
    EnPlusOne Biosciences Inc.)

  • Helena Puig

    (Harvard University
    Massachusetts Institute of Technology)

  • Allison Flores

    (Harvard Medical School
    Harvard University)

  • Subhrajit Rout

    (Harvard Medical School
    Harvard University)

  • Isaac Han

    (Harvard University)

  • Abigail E. Reese

    (The University of Edinburgh)

  • Thomas M. Bartlett

    (Harvard Medical School
    New York State Department of Health)

  • Fabio Moliner

    (The University of Edinburgh)

  • Sylvie G. Bernier

    (Harvard University)

  • Jason D. Galpin

    (The University of Iowa)

  • Jorge Marchand

    (Harvard Medical School
    University of Washington)

  • William Bedell

    (Harvard University)

  • Lindsey Robinson-McCarthy

    (Harvard Medical School)

  • Christopher A. Ahern

    (The University of Iowa)

  • Thomas G. Bernhardt

    (Harvard Medical School
    Howard Hughes Medical Institute)

  • David Z. Rudner

    (Harvard Medical School)

  • James J. Collins

    (Harvard University
    Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard)

  • Marc Vendrell

    (The University of Edinburgh)

  • George M. Church

    (Harvard Medical School
    Harvard University)

Abstract

Binding-activated optical sensors are powerful tools for imaging, diagnostics, and biomolecular sensing. However, biosensor discovery is slow and requires tedious steps in rational design, screening, and characterization. Here we report on a platform that streamlines biosensor discovery and unlocks directed nanosensor evolution through genetically encodable fluorogenic amino acids (FgAAs). Building on the classical knowledge-based semisynthetic approach, we engineer ~15 kDa nanosensors that recognize specific proteins, peptides, and small molecules with up to 100-fold fluorescence increases and subsecond kinetics, allowing real-time and wash-free target sensing and live-cell bioimaging. An optimized genetic code expansion chemistry with FgAAs further enables rapid (~3 h) ribosomal nanosensor discovery via the cell-free translation of hundreds of candidates in parallel and directed nanosensor evolution with improved variant-specific sensitivities (up to ~250-fold) for SARS-CoV-2 antigens. Altogether, this platform could accelerate the discovery of fluorogenic nanosensors and pave the way to modify proteins with other non-standard functionalities for diverse applications.

Suggested Citation

  • Erkin Kuru & Jonathan Rittichier & Helena Puig & Allison Flores & Subhrajit Rout & Isaac Han & Abigail E. Reese & Thomas M. Bartlett & Fabio Moliner & Sylvie G. Bernier & Jason D. Galpin & Jorge March, 2024. "Rapid discovery and evolution of nanosensors containing fluorogenic amino acids," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50956-z
    DOI: 10.1038/s41467-024-50956-z
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    References listed on IDEAS

    as
    1. Sam Benson & Fabio Moliner & Antonio Fernandez & Erkin Kuru & Nicholas L. Asiimwe & Jun-Seok Lee & Lloyd Hamilton & Dirk Sieger & Isabel R. Bravo & Abigail M. Elliot & Yi Feng & Marc Vendrell, 2021. "Photoactivatable metabolic warheads enable precise and safe ablation of target cells in vivo," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Tatenda Mahlokozera & Bhuvic Patel & Hao Chen & Patrick Desouza & Xuan Qu & Diane D. Mao & Daniel Hafez & Wei Yang & Rukayat Taiwo & Mounica Paturu & Afshin Salehi & Amit D. Gujar & Gavin P. Dunn & Ni, 2021. "Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
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