A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins.
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.
|Year of Publication
|PubMed Central ID
R37 GM068649 / GM / NIGMS NIH HHS / United States
F32 GM108294 / GM / NIGMS NIH HHS / United States
S10 OD016326 / OD / NIH HHS / United States
R01 GM110535 / GM / NIGMS NIH HHS / United States
R01 GM046059 / GM / NIGMS NIH HHS / United States
R35 GM122483 / GM / NIGMS NIH HHS / United States
F30 HD093358 / HD / NICHD NIH HHS / United States
F32 GM122204 / GM / NIGMS NIH HHS / United States