Fluorescent amino acids as versatile building blocks for chemical biology

Abstract

Fluorophores have transformed the way we study biological systems, enabling non-invasive studies in cells and intact organisms, which increase our understanding of complex processes at the molecular level. Fluorescent amino acids have become an essential chemical tool because they can be used to construct fluorescent macromolecules, such as peptides and proteins, without disrupting their native biomolecular properties. Fluorescent and fluorogenic amino acids with unique photophysical properties have been designed for tracking protein–protein interactions in situ or imaging nanoscopic events in real time with high spatial resolution. In this Review, we discuss advances in the design and synthesis of fluorescent amino acids and how they have contributed to the field of chemical biology in the past 10 years. Important areas of research that we review include novel methodologies to synthesize building blocks with tunable spectral properties, their integration into peptide and protein scaffolds using site-specific genetic encoding and bioorthogonal approaches, and their application to design novel artificial proteins, as well as to investigate biological processes in cells by means of optical imaging.

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Fig. 1: Applications of FlAAs in chemical biology.
Fig. 2: Representative non-natural FlAAs developed in the past decade.
Fig. 3: Synthetic schemes for the de novo preparation of non-natural FlAAs.
Fig. 4: Bioactive fluorescent peptides for structural studies and optical imaging.
Fig. 5: Fluorescent d-amino acids for studying bacterial growth.
Fig. 6: Genetically encoded site-specific incorporation of FlAAs in live cells.

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Acknowledgements

E.K. acknowledges funding of a fellowship from the Life Sciences Research Foundation. A.S. acknowledges funding from the Wellcome Trust (204593/Z/16/Z) and the Biotechnology and Biological Sciences Research Council (BB/R004692/1). M.V. acknowledges funding from an ERC Consolidator Grant (771443). The authors thank S. Shaikh for the useful comments and technical support with the graphical illustrations.

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Cheng, Z., Kuru, E., Sachdeva, A. et al. Fluorescent amino acids as versatile building blocks for chemical biology. Nat Rev Chem (2020). https://doi.org/10.1038/s41570-020-0186-z

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