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

Yuan Tian, Jingxu Li, Hui Zhao, Xiangze Zeng, Dongyuan Wang, Qisong Liu, Xiaogang Niu, Xuhui Huang, Naihan Xu*, Zigang Li*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

71 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)3325-3330
Number of pages6
JournalChemical Science
Issue number5
Publication statusPublished - 1 May 2016

Scopus Subject Areas

  • Chemistry(all)


Dive into the research topics of 'Stapling of unprotected helical peptides via photo-induced intramolecular thiol–yne hydrothiolation'. Together they form a unique fingerprint.

Cite this