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Anti-apoptotic B cell lymphoma 2 (BCL-2) family proteins are proven targets for human cancers. Targeting the BH3-binding pockets of these anti-apoptotic proteins could reactivate apoptosis in BCL-2-depedent cancers. BFL-1 is a BCL-2 family protein overexpressed in various chemoresistant cancers. A unique cysteine at the binding interface of the BH3 and BFL-1 was previously proven to be an intriguing targeting site to irreversibly inhibit BFL-1 functions with stabilized cyclic peptide bearing a covalent warhead. Recently, we developed a sulfonium-tethered peptide cyclization strategy to construct peptide ligands that could selectively and efficiently react with the cysteine(s) of target proteins near the interacting interface. Using this method, we constructed a BFL-1 peptide inhibitor, B4-MC, that could selectively conjugate with BFL-1 both in vitro and in cell. B4-MC showed good cellular uptake, colocalized with BFL-1 on mitochondria, and showed obvious growth inhibition of BFL-1 over-expressed cancer cell lines. © 2020 Wiley-VCH GmbH.

Citation

Na Liu, Dongyuan Wang, Chenshan Lian, Rongtong Zhao, Licheng Tu, Yichi Zhang, Jianbo Liu, Huilin Zhu, Mengying Yu, Chuan Wan, Di Li, Shuiming Li, Feng Yin, Zigang Li. Selective Covalent Targeting of Anti-apoptotic BFL-1 by a Sulfonium-Tethered Peptide. Chembiochem : a European journal of chemical biology. 2021 Jan 15;22(2):340-344

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PMID: 32790056

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