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

8 Citations (Scopus)

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

Fingerprint

Ubiquitin
Peptides
Cells
Neoplasms
Chemokine Receptors
Antineoplastic Agents
Cell death
Cysteine
Toxicity
Bax protein (53-86)
Permeability
Apoptosis
Ligands

All Science Journal Classification (ASJC) codes

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

Cite this

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
Muppidi, Avinash ; Doi, Kenichiro ; Edwardraja, Selvakumar ; Pulavarti, Surya V.S.R.K. ; Szyperski, Thomas ; Wang, Hong-Gang ; Lin, Qing. / Targeted delivery of ubiquitin-conjugated BH3 peptide-based Mcl-1 inhibitors into cancer cells. In: Bioconjugate Chemistry. 2014 ; Vol. 25, No. 2. pp. 424-432.
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Muppidi, A, Doi, K, Edwardraja, S, Pulavarti, SVSRK, Szyperski, T, Wang, H-G & Lin, Q 2014, 'Targeted delivery of ubiquitin-conjugated BH3 peptide-based Mcl-1 inhibitors into cancer cells', Bioconjugate Chemistry, vol. 25, no. 2, pp. 424-432. https://doi.org/10.1021/bc4005574

Targeted delivery of ubiquitin-conjugated BH3 peptide-based Mcl-1 inhibitors into cancer cells. / Muppidi, Avinash; Doi, Kenichiro; Edwardraja, Selvakumar; Pulavarti, Surya V.S.R.K.; Szyperski, Thomas; Wang, Hong-Gang; Lin, Qing.

In: Bioconjugate Chemistry, Vol. 25, No. 2, 19.02.2014, p. 424-432.

Research output: Contribution to journalArticle

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AU - Szyperski, Thomas

AU - Wang, Hong-Gang

AU - Lin, Qing

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