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A sulfonium tethered peptide ligand rapidly and selectively modifies protein cysteine in vicinity

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Abstract

Significant efforts have been invested to develop site-specific protein modification methodologies in the past two decades. In most cases, a reactive moiety was installed onto ligands with the sole purpose of reacting with specific residues in proteins. Herein, we report a unique peptide macrocyclization method via the bis-alkylation between methionine and cysteine to generate cyclic peptides with significantly enhanced stability and cellular uptake. Notably, when the cyclized peptide ligand selectively recognizes its protein target with a proximate cysteine, a rapid nucleophilic substitution could occur between the protein Cys and the sulfonium center on the peptide to form a conjugate. The conjugation reaction is rapid, facile and selective, triggered solely by proximity. The high target specificity is further proved in cell lysate and hints at its further application in activity based protein profiling. This method enhances the peptide's biophysical properties and generates a selective ligand-directed reactive site for protein modification and fulfills multiple purposes by one modification. This proof-of-concept study reveals its potential for further broad biological applications.

Graphical abstract: A sulfonium tethered peptide ligand rapidly and selectively modifies protein cysteine in vicinity

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Publication details

The article was received on 03 Jan 2019, accepted on 24 Mar 2019 and first published on 25 Mar 2019


Article type: Edge Article
DOI: 10.1039/C9SC00034H
Citation: Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY-NC license
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    A sulfonium tethered peptide ligand rapidly and selectively modifies protein cysteine in vicinity

    D. Wang, M. Yu, N. Liu, C. Lian, Z. Hou, R. Wang, R. Zhao, W. Li, Y. Jiang, X. Shi, S. Li, F. Yin and Z. Li, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C9SC00034H

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