Selection of Natural Peptide Ligands for Copper-Catalyzed Azide-Alkyne Cycloaddition Catalysis

Bioconjugate Chemistry
Allison G AioubM G Finn

Abstract

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is a powerful tool for making connections in both organic reactions and biological systems. However, the use of this ligation process in living cells is limited by the toxicity associated with unbound copper ions. As an initial attempt to create peptide-based accelerating ligands capable of cellular expression, we performed synthesis and selection for such species on solid-phase synthesis beads bearing both candidate ligand and alkyne substrate. A simple histidine-containing motif (HXXH) was identified, and found after solution-phase optimization to produce single-turnover systems showing moderate rate acceleration over the ligand-free reaction. CuAAC reaction rates and yields for different alkynes were found to respond to the peptide ligands, demonstrating a substrate scope beyond what was used for the selection steps, but also illustrating the potential difficulty in evolving a general CuAAC catalyst.

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Citations

May 9, 2018·Chemical Society Reviews·Marc Renom-Carrasco, Laurent Lefort
Jan 4, 2019·Tissue Engineering and Regenerative Medicine·Janarthanan Gopinathan, Insup Noh
Jun 25, 2021·Chemical Reviews·Anand K AgrahariVinod K Tiwari
Nov 24, 2021·Topics in Current Chemistry·Chandan Maity, Nikita Das

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