Development of novel peptides for mitochondrial drug delivery: Amino acids featuring delocalized lipophilic cations

Shana O. Kelley*, Kelly M. Stewart, Rida Mourtada

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2808-2819
Number of pages12
JournalPharmaceutical Research
Volume28
Issue number11
DOIs
StatePublished - Nov 2011
Externally publishedYes

Keywords

  • Cell-penetrating peptides
  • Drug delivery
  • Mitochondria
  • Mitochondria- penetrating peptides

ASJC Scopus subject areas

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

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