Department of Chemistry, State University of New York at Buffalo , Buffalo, New York 14260-3000, United States.
Bioconjug Chem. 2014 Feb 19;25(2):424-32. doi: 10.1021/bc4005574. Epub 2014 Jan 22.
BH3 peptides are key mediators of apoptosis and have served as the lead structures for the development of anticancer therapeutics. Previously, we reported the application of a simple cysteine-based side chain cross-linking chemistry to NoxaBH3 peptides that led to the generation of the cross-linked NoxaBH3 peptides with increased cell permeability and higher inhibitory activity against Mcl-1 ( Muppidi, A., Doi, K., Edwardraja, S., Drake, E. J., Gulick, A. M., Wang, H.-G., Lin, Q. ( 2012 ) J. Am. Chem. Soc. 134 , 14734 ). To deliver cross-linked NoxaBH3 peptides selectively into cancer cells for enhanced efficacy and reduced systemic toxicity, here we report the conjugation of the NoxaBH3 peptides with the extracellular ubiquitin, a recently identified endogenous ligand for CXCR4, a chemokine receptor overexpressed in cancer cells. The resulting ubiquitin-NoxaBH3 peptide conjugates showed increased inhibitory activity against Mcl-1 and selective killing of the CXCR4-expressing cancer cells. The successful delivery of the NoxaBH3 peptides by ubiquitin into cancer cells suggests that the ubiquitin/CXCR4 axis may serve as a general route for the targeted delivery of anticancer agents.
BH3 肽是细胞凋亡的关键介质，已成为开发抗癌治疗药物的主要结构。以前，我们报道了一种简单的半胱氨酸侧链交联化学在 NoxaBH3 肽中的应用，导致交联的 NoxaBH3 肽具有更高的细胞通透性和对 Mcl-1 的更高抑制活性（Muppidi，A.，Doi，K.，Edwardraja，S.，Drake，E. J.，Gulick，A. M.，Wang，H.-G.，Lin，Q.（2012）J. Am. Chem. Soc. 134，14734）。为了将交联的 NoxaBH3 肽选择性递送到癌细胞中以提高疗效和降低全身毒性，我们在这里报告了将 NoxaBH3 肽与细胞外泛素缀合的方法，泛素是最近发现的 CXCR4 的内源性配体，CXCR4 是癌细胞中过表达的趋化因子受体。所得的泛素-NoxaBH3 肽缀合物对 Mcl-1 的抑制活性增加，并且对表达 CXCR4 的癌细胞具有选择性杀伤作用。泛素将 NoxaBH3 肽递送到癌细胞中的成功表明，泛素/CXCR4 轴可能成为靶向递送达癌药物的一般途径。
