Enhanced cellular uptake of short polyarginine peptides through fatty acylation and cyclization

Donghoon Oh, Amir Nasrolahi Shirazi, Kevin Northup, Brian Sullivan, Rakesh Kumar Tiwari, Marco Bisoffi, Keykavous Parang

Research output: Contribution to journalArticle

Abstract

Many of the reported arginine-rich cell-penetrating peptides (CPPs) for the enhanced delivery of drugs are linear peptides composed of more than seven arginine residues to retain the cell penetration properties. Herein, we synthesized a class of nine polyarginine peptides containing 5 and 6 arginines, namely, R5 and R6. We further explored the effect of acylation with long chain fatty acids (i.e., octanoic acid, dodecanoic acid, and hexadecanoic acid) and cyclization on the cell penetrating properties of the peptides. The fluorescence-labeled acylated cyclic peptide dodecanoyl-[R 5] and linear peptide dodecanoyl-(R5) showed approximately 13.7- and 10.2-fold higher cellular uptake than that of control 5,6-carboxyfluorescein, respectively. The mechanism of the peptide internalization into cells was found to be energy-dependent endocytosis. Dodecanoyl-[R5] and dodecanoyl-[R6] enhanced the intracellular uptake of a fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F′-GpYEEI) in human ovarian cancer cells (SK-OV-3) by 3.4-fold and 5.5-fold, respectively, as shown by flow cytometry. The cellular uptake of F′-GpYEEI in the presence of hexadecanoyl-[R 5] was 9.3- and 6.0-fold higher than that in the presence of octanoyl-[R5] and dodecanoyl-[R5], respectively. Dodecanoyl-[R5] enhanced the cellular uptake of the phosphopeptide by 1.4-2.5-fold higher than the corresponding linear peptide dodecanoyl-(R 5) and those of representative CPPs, such as hepta-arginine (CR 7) and TAT peptide. These results showed that a combination of acylation by long chain fatty acids and cyclization on short arginine-containing peptides can improve their cell-penetrating property, possibly through efficient interaction of rigid positively charged R and hydrophobic dodecanoyl moiety with the corresponding residues in the cell membrane phospholipids.

Original languageEnglish (US)
Pages (from-to)2845-2854
Number of pages10
JournalMolecular Pharmaceutics
Volume11
Issue number8
DOIs
StatePublished - Aug 4 2014
Externally publishedYes

Keywords

  • acylation
  • cyclic peptide
  • cyclization
  • drug delivery
  • polyarginine

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery
  • Medicine(all)

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  • Cite this

    Oh, D., Nasrolahi Shirazi, A., Northup, K., Sullivan, B., Tiwari, R. K., Bisoffi, M., & Parang, K. (2014). Enhanced cellular uptake of short polyarginine peptides through fatty acylation and cyclization. Molecular Pharmaceutics, 11(8), 2845-2854. https://doi.org/10.1021/mp500203e