Issue 19, 2019

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

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

Supplementary files

Article information

Article type
Edge Article
Submitted
03 jan 2019
Accepted
24 mrt 2019
First published
25 mrt 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2019,10, 4966-4972

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, 10, 4966 DOI: 10.1039/C9SC00034H

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