caa a22 4500 445314451 CHVBK 20180317142641.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s11095-011-0530-6 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0530-6 Development of Novel Peptides for Mitochondrial Drug Delivery: Amino Acids Featuring Delocalized Lipophilic Cations [Elektronische Daten] [Shana Kelley, Kelly Stewart, Rida Mourtada] ABSTRACT: Purpose: To create a new class of mitochondria-penetrating peptides (MPPs) that would facilitate drug delivery into the organelle through the inclusion of delocalized lipophilic cations (DLCs) in the peptide sequence. Methods: We synthesized two novel amino acids featuring DLCs and incorporated them into peptides. Systematic studies were conducted to compare peptides containing these residues to those with natural cationic amino acids. Diastereomers were compared to determine the most advantageous arrangement for these peptides. Peptide lipophilicity, cellular uptake and mitochondrial specificity were compared for a variety of peptides. Results: Synthetic DLC residues were found to increase mitochondrial localization of MPPs due to higher overall hydrophobicity. MPP stereochemistry was important for cellular uptake rather than subcellular localization. This study reaffirmed the importance of uniform overall charge distribution for mitochondrial specificity. Conclusions: DLCs can be incorporated into synthetic peptides and facilitate mitochondrial drug delivery. Lipophilicity and charge distribution must be carefully balanced to ensure localization within mitochondria. Springer Science+Business Media, LLC, 2011 cell-penetrating peptides nationallicence drug delivery nationallicence mitochondria nationallicence mitochondria-penetrating peptides nationallicence CPP : cell-penetrating peptide nationallicence DLC : delocalized lipophilic cation nationallicence MPP : mitochondria-penetrating peptide nationallicence Kelley Shana Department of Biochemistry, Faculty of Medicine, University of Toronto, M5S 3M2, Toronto, Canada aut Stewart Kelly Department of Biochemistry, Faculty of Medicine, University of Toronto, M5S 3M2, Toronto, Canada aut Mourtada Rida Department of Pharmaceutical Sciences Leslie Dan Faculty of Pharmacy, University of Toronto, M5S 3M2, Toronto, Canada aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/11(2011-11-01), 2808-2819 0724-8741 28:11<2808 2011 28 11095 https://doi.org/10.1007/s11095-011-0530-6 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0530-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kelley Shana Department of Biochemistry, Faculty of Medicine, University of Toronto, M5S 3M2, Toronto, Canada aut NATIONALLICENCE 700 1- Stewart Kelly Department of Biochemistry, Faculty of Medicine, University of Toronto, M5S 3M2, Toronto, Canada aut NATIONALLICENCE 700 1- Mourtada Rida Department of Pharmaceutical Sciences Leslie Dan Faculty of Pharmacy, University of Toronto, M5S 3M2, Toronto, Canada aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/11(2011-11-01), 2808-2819 0724-8741 28:11<2808 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer