Targeted delivery of ubiquitin-conjugated BH3 peptide-based Mcl-1 inhibitors into cancer cells
- Bioconjug Chem. 2014 Feb 19;25(2):424-32. doi: 10.1021/bc4005574.
- 1. Department of Chemistry, State University of New York at Buffalo , Buffalo, New York 14260-3000, United States.
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.