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Issue 6, 2016
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Rapid biocompatible macrocyclization of peptides with decafluoro-diphenylsulfone

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Abstract

In this manuscript, we describe modification of Cys-residues in peptides and proteins in aqueous solvents via aromatic nucleophilic substitution (SNAr) with perfluoroarenes (fAr). Biocompatibility of this reaction makes it attractive for derivatization of proteins and peptide libraries comprised of 20 natural amino acids. Measurement of the reaction rates for fAr derivatives by 19F NMR with a model thiol donor (β-mercaptoethanol) in aqueous buffers identified decafluoro-diphenylsulfone (DFS) as the most reactive SNAr electrophile. Reaction of DFS with thiol nucleophiles is >100 000 faster than analogous reaction of perfluorobenzene; this increase in reactivity enables application of DFS at low concentrations in aqueous solutions compatible with biomolecules and protein complexes irreversibly degraded by organic solvents (e.g., bacteriophages). DFS forms macrocycles when reacted with peptides of the general structure Xn–Cys–Xm–Cys–Xl, where X is any amino acid and m = 1–15. It formed cyclic peptides with 6 peptide hormones—oxytocin, urotensin II, salmon calcitonin, melanin-concentrating hormone, somatostatin-14, and atrial natriuretic factor (1–28) as well as peptides displayed on M13 phage. Rates up to 180 M−1 s−1 make this reaction one of the fastest Cys-modifications to-date. Long-term stability of macrocycles derived from DFS and their stability toward oxidation further supports DFS as a promising method for modification of peptide-based ligands, cyclization of genetically-encoded peptide libraries, and discovery of bioactive macrocyclic peptides.

Graphical abstract: Rapid biocompatible macrocyclization of peptides with decafluoro-diphenylsulfone

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Publication details

The article was received on 11 Oct 2015, accepted on 19 Feb 2016 and first published on 19 Feb 2016


Article type: Edge Article
DOI: 10.1039/C5SC03856A
Citation: Chem. Sci., 2016,7, 3785-3790
  • Open access: Creative Commons BY-NC license
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    Rapid biocompatible macrocyclization of peptides with decafluoro-diphenylsulfone

    S. Kalhor-Monfared, M. R. Jafari, J. T. Patterson, P. I. Kitov, J. J. Dwyer, J. M. Nuss and R. Derda, Chem. Sci., 2016, 7, 3785
    DOI: 10.1039/C5SC03856A

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