Multiple triphenylphosphonium cations as a platform for the delivery of a pro-apoptotic peptide

Netanel Kolevzon, Uriel Kuflik, Miriam Shmuel, Sandrine Benhamron, Israel Ringel, Eylon Yavin

Research output: Contribution to journalArticlepeer-review


Purpose: Triphenyl phosphonium cations (TPPs) are delocalized lipophilic cations that accumulate in the mitochondria of cells. We have explore the effect of increasing the number of TPPs on delivery of a cell-impermeable pro-apoptotic peptide to intact cells. Methods: The pro-apoptotic peptide D-(KLAKLAK) 2 (KLA) was extended with 0-3 L-Lysines modified at their ε-amine with TPP. Peptides were studied in HeLa cells to determine their cytotoxic activity and cellular uptake. Results: In HeLa cells, the increased cytotoxicity correlates with the number of TPPs; the peptide with 3 TPP molecules (3-KLA) exerts the highest cytotoxic activity. This FITC-labeled peptide is found to accumulate in intact HeLa cells, whereas peptides with 0-2 TPPs are not detected at the same peptide concentration. Mitochondria-dependent apoptosis of HeLa cells in the presence of 3-KLA was followed by propidium iodide, Annexin-V and DiOC fluorescence by FACS. Conclusion: A facile synthetic methodology has been presented for the delivery of a biologically active peptide into mitochondria of intact cells by attaching multiple TPP moieties to the peptide. This approach was shown to dramatically increase biological activity of the peptide as a pro-apoptotic agent.

Original languageAmerican English
Pages (from-to)2780-2789
Number of pages10
JournalPharmaceutical Research
Issue number11
StatePublished - Nov 2011


  • Antimicrobial peptide
  • Apoptosis
  • Mitochondria
  • Tripenylphosphonium

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)
  • Molecular Medicine
  • Biotechnology
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry


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