caa a22 4500 445314397 CHVBK 20180317142641.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s11095-011-0494-6 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0494-6 Multiple Triphenylphosphonium Cations as a Platform for the Delivery of a Pro-Apoptotic Peptide [Elektronische Daten] [Netanel Kolevzon, Uriel Kuflik, Miriam Shmuel, Sandrine Benhamron, Israel Ringel, Eylon Yavin] ABSTRACT: 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. Springer Science+Business Media, LLC, 2011 antimicrobial peptide nationallicence apoptosis nationallicence mitochondria nationallicence tripenylphosphonium nationallicence Ahx : 6-aminohexanoicacid nationallicence Alloc : allyloxycarbonyl nationallicence FITC : fluorescein isothiocyanate nationallicence PI : propidium iodide nationallicence TPP : triphenylphosphonium nationallicence Kolevzon Netanel Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut Kuflik Uriel Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut Shmuel Miriam Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut Benhamron Sandrine Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut Ringel Israel Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut Yavin Eylon Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/11(2011-11-01), 2780-2789 0724-8741 28:11<2780 2011 28 11095 https://doi.org/10.1007/s11095-011-0494-6 text/html Onlinezugriff via DOI 1 review-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0494-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kolevzon Netanel Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut NATIONALLICENCE 700 1- Kuflik Uriel Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut NATIONALLICENCE 700 1- Shmuel Miriam Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut NATIONALLICENCE 700 1- Benhamron Sandrine Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut NATIONALLICENCE 700 1- Ringel Israel Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut NATIONALLICENCE 700 1- Yavin Eylon Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/11(2011-11-01), 2780-2789 0724-8741 28:11<2780 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer