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Liu, Y.* ; Arus, B.A. ; Mishra, K. ; Wang, T.* ; Zhang, K.* ; Luciano, M.P.* ; Bandi, V.G.* ; Kumar, A.* ; Guo, Z.* ; Guan, Y.* ; Bick, M.J.* ; Xu, M.* ; Lingg, J.G.P. ; Bae, J.* ; Kang, A.* ; Gerben, S.R.* ; Bera, A.K.* ; Vaughan, J.C.* ; Manton, J.D.* ; Derivery, E.* ; Schnermann, M.J.* ; Stiel, A.-C. ; Bruns, O.T. ; Xu, C.* ; Baker, D.*

De novo design of near-infrared fluorescence-activating proteins.

J. Am. Chem. Soc. 148, 23530-23539 (2026)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Protein-based fluorescence imaging is a powerful modality for visualizing diverse biological processes. Biological imaging in the near-infrared (NIR, 800-1000 nm) and shortwave infrared (SWIR, 1000-2000 nm) ranges confers a number of photophysical advantages, but remains a challenge in practice due to the dearth of suitable protein probes in these optical windows. To address this limitation, we sought to develop a general approach integrating computational protein design with organic synthesis for creating long-wavelength fluorescence-activating proteins from scratch. We used this approach to de novo design proteins that specifically bind to synthetic merocyanine dyes, forming Schiff base covalent linkages, which when protonated activate fluorescence with large redshifts in both excitation and emission wavelengths. We describe a designed far-red fluorescence-activating protein, MC7BP34, with a brightness greater than that of existing fluorescent proteins in a similar wavelength range, and an NIR design MC9BP81 with excitation at 892 nm and emission extending into the SWIR range with higher contrast and imaging sensitivity in vivo than the previously developed iRFP720 (excitation 672 nm) owing to the reduced tissue autofluorescence at longer wavelengths. Our results are a substantial step toward genetically encodable probes in the SWIR region, and our approach lays the groundwork for the development of NIR biosensors for specific biological applications.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Molecule
ISSN (print) / ISBN 0002-7863
e-ISSN 1520-5126
Journal Journal of the American Chemical Society
Quellenangaben Volume: 148, Issue: 23, Pages: 23530-23539 Article Number: , Supplement: ,
Publisher American Chemical Society (ACS)
Publishing Place 1155 16th St, Nw, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Institute(s) Helmholtz Pioneer Campus (HPC)
Institute of Biological and Medical Imaging (IBMI)
Grants Advanced Research Projects Agency for Health
National Key Research and Development Program of China
Bill and Melinda Gates Foundation
Institute for Protein Design, University of Washington
National Cancer Institute
Medical Research Council
Howard Hughes Medical Institute
Human Frontier Science Program