Manipulating the Click Reactivity of Dibenzoazacyclooctynes: From Azide Click Component to Caged Acylation Reagent by Silver Catalysis

Abstract

Strain-promoted azide-alkyne cycloaddition using dibenzoazacyclooctyne (DBCO) is widely applied in copperfree bioorthogonal reactions. Reported here is the efficient acid-promoted rearrangement and silver-catalyzed amidation of DBCO, which alters its click reactivity robustly. In the switched click reaction, DBCO, as a caged acylation reagent, enables rapid peptide/protein modification after decaging facilitated by silver catalysts, rendering site-specific conjugation of an IgG antibody by a Fc-targeting peptide.

Insulin‐like Growth Factor 2‐Tagged Aptamer Chimeras (ITACs) Modular Assembly for Targeted and Efficient Degradation of Two Membrane Proteins

“…Aptamers are oligonucleotides that can specifically bind to various protein targets and show advantages including ease of synthesis, low cost and high chemical stability compared to antibodies and small molecules [7] . Covalent linking between IGF2 and aptamer mediated by easy‐to‐use “click” chemistry specifically delivered target membrane proteins to lysosome and resulted in effective targeted protein degradation [12] . We further systematically studied the relationship between cell‐surface IGF2R protein level and degradation efficiency of ITACs, and found that targeted degradation of cell‐surface protein was only achieved in cell lines with a moderate IGF2R protein level, while either a low or high level of IGF2R lead to low degradation efficiency.…”

“…[7] Covalent linking between IGF2 and aptamer mediated by easy-to-use "click" chemistry specifically delivered target membrane proteins to lysosome and resulted in effective targeted protein degradation. [12] We further systematically studied the relationship between cell-surface IGF2R protein level and degradation efficiency of ITACs, and found that targeted degradation of cell-surface protein was only achieved in cell lines with a moderate IGF2R protein level, while either a low or high level of IGF2R lead to low degradation efficiency. Furthermore, by conjugating a linker DNA to IGF2 and extending aptamers with pieces of complementary DNA, modular assembly of ITACs with precise stoichiometry of two aptamers targeting different cell membrane proteins was achieved.…”