Rapid discovery and evolution of nanosensors containing fluorogenic amino acids

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 Marchand, William Bedell, Lindsey Robinson-McCarthy, Christopher A. Ahern, Thomas G. Bernhardt, David Z. Rudner, James J. Collins, Marc Vendrell () and George M. Church ()
Additional contact information
Erkin Kuru: Harvard Medical School
Jonathan Rittichier: Harvard Medical School
Helena Puig: Harvard University
Allison Flores: Harvard Medical School
Subhrajit Rout: Harvard Medical School
Isaac Han: Harvard University
Abigail E. Reese: The University of Edinburgh
Thomas M. Bartlett: Harvard Medical School
Fabio Moliner: The University of Edinburgh
Sylvie G. Bernier: Harvard University
Jason D. Galpin: The University of Iowa
Jorge Marchand: Harvard Medical School
William Bedell: Harvard University
Lindsey Robinson-McCarthy: Harvard Medical School
Christopher A. Ahern: The University of Iowa
Thomas G. Bernhardt: Harvard Medical School
David Z. Rudner: Harvard Medical School
James J. Collins: Harvard University
Marc Vendrell: The University of Edinburgh
George M. Church: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50956-z

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