A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins
Author(s)
Cohen, Daniel Tzvi; Zhang, Chi; Fadzen, Colin M.; Mijalis, Alexander James; Hie, Liana; Johnson, Kenneth D.; Shriver, Zachary; Plante, Obadiah; Miller, Scott J.; Buchwald, Stephen Leffler; Pentelute, Bradley L.; ... Show more Show less
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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. Keywords: biomaterials – protein; chemical modification; proteins
Date issued
2018-11Department
Massachusetts Institute of Technology. Department of ChemistryJournal
Nature Chemistry
Publisher
Springer Science and Business Media LLC
Citation
Cohen, Daniel T. et al. "A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins." Nature Chemistry 11, 1 (November 2018): 78–85 © 2018, The Author(s), under exclusive licence to Springer Nature Limited
Version: Author's final manuscript
ISSN
1755-4330
1755-4349