Selective Covalent Targeting of Anti-apoptotic BFL-1 by a Sulfonium-Tethered Peptide

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.

Automated summary

Anti-apoptotic BCL-2 family proteins are important targets for cancer treatment, and targeting the BH3-binding pockets can reactivate apoptosis. A novel sulfonium-tethered peptide cyclization strategy was developed to selectively bind to the cysteine(s) of target proteins, leading to the successful construction of a BFL-1 peptide inhibitor, B4-MC, showing promising growth inhibition of BFL-1 over-expressed cancer cell lines.