Targeted delivery of ubiquitin-conjugated BH3 peptide-based Mcl-1 inhibitors into cancer cells

Avinash Muppidi, Kenichiro Doi, Selvakumar Edwardraja, Surya V.S.R.K. Pulavarti, Thomas Szyperski, Hong Gang Wang, Qing Lin

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)424-432
Number of pages9
JournalBioconjugate Chemistry
Volume25
Issue number2
DOIs
StatePublished - Feb 19 2014

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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    Muppidi, A., Doi, K., Edwardraja, S., Pulavarti, S. V. S. R. K., Szyperski, T., Wang, H. G., & Lin, Q. (2014). Targeted delivery of ubiquitin-conjugated BH3 peptide-based Mcl-1 inhibitors into cancer cells. Bioconjugate Chemistry, 25(2), 424-432. https://doi.org/10.1021/bc4005574