State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Room 301, Building E, Xili University, Shenzhen, P. R. China.
Pingshan Translational Medicine Center, Shenzhen Bay Laboratory5F, No.9, Duxue Road, Nanshan, Shenzhen, P. R. China.
Chembiochem. 2021 Jan 15;22(2):340-344. doi: 10.1002/cbic.202000473. Epub 2020 Oct 1.
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.
抗凋亡 B 细胞淋巴瘤 2（BCL-2）家族蛋白已被证实为人类癌症的靶点。针对这些抗凋亡蛋白的 BH3 结合口袋进行靶向治疗，可以在依赖 BCL-2 的癌症中重新激活细胞凋亡。BFL-1 是一种在各种耐药性癌症中过度表达的 BCL-2 家族蛋白。以前已经证明，BH3 和 BFL-1 结合界面上的一个独特半胱氨酸是一个有趣的靶向位点，可以用带有共价弹头的稳定环肽不可逆地抑制 BFL-1 的功能。最近，我们开发了一种带正电荷的肽环化策略来构建肽配体，这些配体可以选择性和有效地与相互作用界面附近的靶蛋白的半胱氨酸反应。使用这种方法，我们构建了一种 BFL-1 肽抑制剂 B4-MC，它可以在体外和细胞内选择性地与 BFL-1 结合。B4-MC 具有良好的细胞摄取能力，与线粒体上的 BFL-1 共定位，并对 BFL-1 过表达的癌细胞系表现出明显的生长抑制作用。
