title: Development of novel peptides for mitochondrial drug delivery: amino acids featuring delocalized lipophilic cations.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto M5S 3M2, Canada. shana.kelley@utoronto.ca
authors.forename: Shana O
authors.initials: SO
authors.lastname: Kelley
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Stewart
authors.forename: Rida
authors.initials: R
authors.lastname: Mourtada
mesh_terms: D000596:Amino Acids / Q000032:analysis / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002412:Cations / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D018929:Cell Culture Techniques; D057846:Cell-Penetrating Peptides / Q000032:analysis / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008928:Mitochondria / Q000737:chemistry* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D012680:Sensitivity and Specificity
chemical_list: D000596:Amino Acids; D002412:Cations; D057846:Cell-Penetrating Peptides