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 language | English (US) |
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Pages (from-to) | 2449-2453 |
Number of pages | 5 |
Journal | ChemMedChem |
Volume | 9 |
Issue number | 11 |
DOIs | |
State | Published - Nov 1 2014 |
Externally published | Yes |
Keywords
- amphiphiles
- bicyclic peptides
- cell-penetrating
- drug delivery
- endocytosis
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Organic Chemistry
- Molecular Medicine
- Medicine(all)