title: Targeted delivery of ubiquitin-conjugated BH3 peptide-based Mcl-1 inhibitors into cancer cells.
abstract: 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.
authors.affiliation: Department of Chemistry, State University of New York at Buffalo , Buffalo, New York 14260-3000, United States.
authors.forename: Avinash
authors.initials: A
authors.lastname: Muppidi
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Doi
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Edwardraja
authors.forename: Surya V S R K
authors.initials: SV
authors.lastname: Pulavarti
authors.forename: Thomas
authors.initials: T
authors.lastname: Szyperski
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D005454:Fluorescence Polarization; D006801:Humans; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000473:pathology*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage* / Q000737:chemistry; D025801:Ubiquitin / Q000737:chemistry*
chemical_list: C474007:Bax protein (53-86); C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin