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Nat Chem. 2019 Jan;11(1):78-85. doi: 10.1038/s41557-018-0154-0. Epub 2018 Nov 5.

A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins.

Author information

1
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. daniel.t.cohen@abbvie.com.
2
AbbVie, Inc., North Chicago, IL, USA. daniel.t.cohen@abbvie.com.
3
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
4
Department of Chemistry, Yale University, New Haven, CT, USA.
5
Visterra Inc., Cambridge, MA, USA.
6
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. blp@mit.edu.
7
Koch Institute, Broad Institute of Harvard and MIT, Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. blp@mit.edu.

Abstract

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‚ÄČkDa affibody protein and a 150‚ÄČkDa immunoglobulin-G antibody could be modified without diminishing bioactivity.

PMID:
30397320
PMCID:
PMC6454892
[Available on 2020-01-01]
DOI:
10.1038/s41557-018-0154-0
[Indexed for MEDLINE]

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