Journal
PHARMACEUTICAL RESEARCH
Volume 28, Issue 11, Pages 2780-2789Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-011-0494-6
Keywords
antimicrobial peptide; apoptosis; mitochondria; tripenylphosphonium
Funding
- Israel Cancer Association
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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. The pro-apoptotic peptide D-(KLAKLAK)(2) (KLA) was extended with 0-3 L-Lysines modified at their epsilon-amine with TPP. Peptides were studied in HeLa cells to determine their cytotoxic activity and cellular uptake. 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. 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.
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