Cell-penetrating peptides (CPPs) have been studied as molecular transporters because of their cellular translocation properties. Among CPPs, cyclic peptides take advantage of their higher serum stability compared to the linear counterparts. In addition, the presence of positively charged arginine and hydrophobic tryptophan amino acids were found to be critical due to their characteristic interactions with phospholipid membranes. Here, two bicyclic peptides [W5G]-(triazole)-[KR5] and [W5E]-(�-Ala)-[KR5] composed of tryptophan and arginine residues were synthesized from monocyclic peptide building blocks and evaluated as cellular delivery agents. [W5G]-(triazole)-[KR5] and [W5E]-(�-Ala)-[KR5] containing triazole and �-alanine linkers improved the cellular delivery of fluorescein-labelled phosphopeptide, F'-GpYEEI by 7.6 and 19.3-fold, respectively, in human ovarian adenocarcinoma (SK-OV-3) cells. Confocal microscopy showed that the corresponding fluorescein-labelled bicyclic peptide F'-[KW4E]-(�-Ala)-[KR5] was localized in the cytosol and nucleus. Studying the cellular uptake of F'-[KW4E]-(�-Ala)-[KR5] in the presence of endocytosis inhibitors indicated that the clathrin- and caveolin-dependent endocytosis were the main pathways for cellular uptake. The bicyclic peptide was able to improve antiproliferative activity of doxorubicin by 20%. These data suggest that amphiphilic bicyclic peptides containing tryptophan and arginine residues can be utilized as a new class of cell-penetrating peptides and potential cellular delivery tools.

Amphiphilic bicyclic peptides as cellular delivery agents

248th National Meeting (2014)

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