Abstract
The ability to construct a peptide or protein in a spatio-specific manner is of great interest for therapeutic and biochemical research. However, the various functional groups present in peptide sequences and the need to perform chemistry under mild and aqueous conditions make selective protein functionalization one of the greatest synthetic challenges. The fascinating paradox of selenium (Se) — being found in both toxic compounds and also harnessed by nature for essential biochemical processes — has inspired the recent exploration of selenium chemistry for site-selective functionalization of peptides and proteins. In this Review, we discuss such approaches, including metal-free and metal-catalysed transformations, as well as traceless chemical modifications. We report their advantages, limitations and applications, as well as future research avenues.
Key points
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Se chemistry can be used for peptide and protein modifications in a site-selective manner.
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Se chemistry can be performed effectively and efficiently and in a traceless manner, that is, Se can be eliminated selectively upon protein spatio-specific protein functionalization.
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Regioselective diselenide bond formation has a tremendous effect on protein folding, stability and solubility, which can be useful for therapeutic protein applications.
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The development of the Se-based chemistry for spatio-specific manipulation of peptides and proteins has a tremendous potential for in vitro and in vivo targeting in the field of chemical biology and therapeutic developments.
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Acknowledgements
The authors wish to thank members of the Metanis group for the helpful discussions. N.M. thanks the support from the Israel Science Foundation (1388/22). S.L. is supported by the Emergency Postdoctoral Fellowships for Israeli Researchers in Israel of the Israel Academy of Sciences and Humanities.
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The authors Z.Z. and S.L. contributed equally to all aspects of the article. N.M. conceived and supervised the writing. All authors researched data and wrote the article.
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Zhao, Z., Laps, S., Gichtin, J.S. et al. Selenium chemistry for spatio-selective peptide and protein functionalization. Nat Rev Chem 8, 211–229 (2024). https://doi.org/10.1038/s41570-024-00579-1
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DOI: https://doi.org/10.1038/s41570-024-00579-1