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Issue 5, 2016
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Stapling of unprotected helical peptides via photo-induced intramolecular thiol–yne hydrothiolation

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Abstract

Peptide stapling emerged as a versatile strategy to recapitulate the bioactive helical conformation of unstructured short peptides in water to improve their therapeutic properties in targeting intracellular “undruggable” targets. Here, we describe the development of photo-induced intramolecular thiol–yne macrocyclization for rapid access to short stapled peptides with enhanced biophysical properties. This new peptide stapling technique provides rapid access to conformationally constrained helices with satisfying functional group tolerance. Notably, the vinyl sulfide linkage shows distinct lipophilicity with reduced membrane toxicity compared to the corresponding all-hydrocarbon analogue. As a proof of principle, we constructed stabilized helices modulating intracellular estrogen receptor (ER)–coactivator interactions with a nanomolar binding affinity, enhanced serum stability, a diffuse cellular distribution and selective cytotoxicity towards ER-positive MCF-7 cells.

Graphical abstract: Stapling of unprotected helical peptides via photo-induced intramolecular thiol–yne hydrothiolation

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Publication details

The article was received on 08 Jan 2016, accepted on 03 Feb 2016 and first published on 05 Feb 2016


Article type: Edge Article
DOI: 10.1039/C6SC00106H
Citation: Chem. Sci., 2016,7, 3325-3330
  • Open access: Creative Commons BY-NC license
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    Stapling of unprotected helical peptides via photo-induced intramolecular thiol–yne hydrothiolation

    Y. Tian, J. Li, H. Zhao, X. Zeng, D. Wang, Q. Liu, X. Niu, X. Huang, N. Xu and Z. Li, Chem. Sci., 2016, 7, 3325
    DOI: 10.1039/C6SC00106H

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