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 has presented 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 prefunctionalization of vancomycin. These conjugates had enhanced in vitro potency for resistant Gram-positive and Gram-negative pathogens. Additionally, we showed that a 6 kDa affibody protein and a 150 kDa IgG antibody could be modified without diminishing bioactivity.

Palladium‐Mediated Cleavage of Proteins with Thiazolidine‐Modified Backbone in Live Cells

“…Chemical and semisynthesis of proteins,asexamples to these approaches,c ombine the power of solid-phase peptide synthesis (SPPS) and chemoselective ligation strategies to construct the polypeptide chain corresponding to af olded protein. [4][5][6][7] Regardless of the synthetic approach, the majority of modified proteins have been achieved by specific modification of amino-acid side chains,l eaving backbone modifications underexplored. [3] Late-stage modification of proteins enables further manipulations,t hus expanding their structural diversity.…”

Chemical Methods for Selective Labeling of Proteins

“…The capability of tetrazine to enable inverse‐electron‐demand Diels‐Alder reaction was also harnessed by Guo and co‐workers through a pre‐engineered styrene (ncAA) . In an interesting report, Pentelute's group synthesized proteins with an electrophilic selenium group primed for late‐stage installation of probes (Scheme e) …”

Selenocystine Peptides Performance in 5‐endo‐dig Reactions

“…Another sulfur‐containing oxidant (persulfates) induced generation of selenium electrophile has been used for the direct selenylation of indole and arenofurans . It is noteworthy that previous research has only focused on the use of simple diaryl diselenides except for Cohen et al who reported a sophisticated method, for the generation of selenocysteine, (Sec, U) electrophile. This approach is based on the electrophilic character of (5‐nitropyridylthio)‐Sec peptides and was used in Sec‐peptide and small molecule (including some indoles) late stage conjugation.…”