Amphiphilic bicyclic peptides as cellular delivery agents

Donghoon Oh, Shaban Anwar Darwish, Amir Nasrolahi Shirazi, Rakesh Kumar Tiwari, Keykavous Parang

Research output: Contribution to journalArticle

Abstract

Two bicyclic peptides composed of tryptophan and arginine residues were synthesized from monocyclic peptide building blocks and evaluated as cellular delivery agents. [W5G]-(triazole)-[KR5] and [W5E]-(β-Ala)-[KR5] containing triazole and β-alanine linkers improved the cellular delivery of fluorescein (F')-labeled phosphopeptide F'-GpYEEI (F'-PP) by 7.6-and 19.3-fold, respectively, in human ovarian adenocarcinoma cells. However, parent monocyclic peptide [R5] and monocyclic peptide [WR]4 only enhanced the cellular uptake of the phosphopeptide by only 1.3-and 3.7-fold, respectively. Confocal microscopy showed that the corresponding fluorescein-labeled bicyclic peptide F'-[KW4E]-(β-Ala)-[KR5] was localized in the cytosol and nucleus. Studying the cellular uptake of F'-[KW4E]-(β-Ala)-[KR5] in the presence of endocytosis inhibitors indicated that the clathrin-and caveolin-dependent endocytosis are the main pathways for cellular uptake. The bicyclic peptide was able to improve antiproliferative activity of doxorubicin by 20 %. These data suggest that this bicyclic peptide can be utilized as a new class of cell-penetrating peptides and cellular delivery tools.

Original languageEnglish (US)
Pages (from-to)2449-2453
Number of pages5
JournalChemMedChem
Volume9
Issue number11
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

Keywords

  • amphiphiles
  • bicyclic peptides
  • cell-penetrating
  • drug delivery
  • endocytosis

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine
  • Medicine(all)

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  • Cite this

    Oh, D., Darwish, S. A., Shirazi, A. N., Tiwari, R. K., & Parang, K. (2014). Amphiphilic bicyclic peptides as cellular delivery agents. ChemMedChem, 9(11), 2449-2453. https://doi.org/10.1002/cmdc.201402230