Conjugates between proteins and small molecules enable access to a vast chemical space that is not achievable with either type of molecule alone; however, the paucity of specific reactions capable of functionalizing proteins and natural products presents a formidable challenge for preparing conjugates. Here we report a strategy for conjugating electron-rich (hetero)arenes to polypeptides and proteins. Our bioconjugation technique exploits the electrophilic reactivity of an oxidized selenocysteine residue in polypeptides and proteins, and the electron-rich character of certain small molecules to provide bioconjugates in excellent yields under mild conditions. This conjugation chemistry enabled the synthesis of peptide–vancomycin conjugates without the prefunctionalization of vancomycin. These conjugates have an enhanced in vitro potency for resistant Gram-positive and Gram-negative pathogens. Additionally, we show that a 6 kDa affibody protein and a 150 kDa immunoglobulin-G antibody could be modified without diminishing bioactivity.
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All the data generated or analysed during this study are included in this published article (and in the Supplementary Information). Further details are available from the corresponding authors upon request.
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Financial support was provided by NIH Awards GM46059 (S.L.B.), F32GM108294 (D.T.C.), F32GM122204 (L.H.), F30HD093358 (C.M.F.) and GM110535 (B.L.P.) and also by MIT startup funds, a Damon Runyon Cancer Research Foundation Award and a Sontag Distinguished Scientist Award for B.L.P. C.Z. is a recipient of a George Büchi Summer Research Fellowship, a Koch Graduate Fellowship in Cancer Research and a Bristol-Myers Squibb Fellowship in Synthetic Organic Chemistry. A.J.M. is a National Science Foundation Graduate Research Fellow. The authors acknowledge the Biological Instrument Facility of MIT for providing the Octet BioLayer Interferometry System (NIH S10 OD016326) and CD spectrometer (NSF-0070319). We thank Y.-M. Wang and M. Pirnot (MIT) for help in preparing this article. We also acknowledge S. Bano (Merck) for Cu ICP-MS analysis of the purified peptides 13c, 13d, 13e and 13f.
K.D.J., Z.S. and O.P. are employees of Visterra Inc. D.T.C., C.Z., S.L.B. and B.L.P. are inventors on a patent filed by MIT-TLO to cover this work (US patent application no. 15,187,169 and international application (PCT/US16/38372).
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Cohen, D.T., Zhang, C., Fadzen, C.M. et al. A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins. Nature Chem 11, 78–85 (2019). https://doi.org/10.1038/s41557-018-0154-0
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