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Nat Commun. 2018 Jul 20;9(1):2847. doi: 10.1038/s41467-018-05264-8.

Accelerated microfluidic native chemical ligation at difficult amino acids toward cyclic peptides.

Author information

1
UMR CNRS 8204, Chemical Biology of Flatworms, Institut Pasteur de Lille, Université de Lille, 1 rue du Pr Calmette, 59021, Lille Cedex, France.
2
Department of Chemistry, RU Molecular Systems, Center for Integrated Technology and Organic Synthesis, University of Liège, B-4000, Liège (Sart Tilman), Belgium.
3
INSERM U1019 UMR CNRS 8204, Chemical Biology of Antibiotics, Institut Pasteur de Lille, Université de Lille, 1 rue du Pr Calmette, 59021, Lille Cedex, France.
4
Department of Chemistry, RU Molecular Systems, Center for Integrated Technology and Organic Synthesis, University of Liège, B-4000, Liège (Sart Tilman), Belgium. jc.monbaliu@uliege.be.
5
UMR CNRS 8204, Chemical Biology of Flatworms, Institut Pasteur de Lille, Université de Lille, 1 rue du Pr Calmette, 59021, Lille Cedex, France. oleg.melnyk@ibl.cnrs.fr.

Abstract

Cyclic peptide-based therapeutics have a promising growth forecast that justifies the development of microfluidic systems dedicated to their production, in phase with the actual transitioning toward continuous flow and microfluidic technologies for pharmaceutical production. The application of the most popular method for peptide cyclization in water, i.e., native chemical ligation, under microfluidic conditions is still unexplored. Herein, we report a general strategy for fast and efficient peptide cyclization using native chemical ligation under homogeneous microfluidic conditions. The strategy relies on a multistep sequence that concatenates the formation of highly reactive S-(2-((2-sulfanylethyl)amino)ethyl) peptidyl thioesters from stable peptide amide precursors with an intramolecular ligation step. With very fast ligation rates (<5 min), even for the most difficult junctions (including threonine, valine, isoleucine, or proline), this technology opens the door toward the scale-independent, expedient preparation of bioactive macrocyclic peptides.

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