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

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

SUBMITTER: Cohen DT 

PROVIDER: S-EPMC6454892 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature