Amphiphilic Bicyclic Peptides as Cellular Delivery Agents

作者：Oh Donghoon^*; Darwish Shaban Anwar; Shirazi Amir Nasrolahi; Tiwari Rakesh Kumar; Parang Keykavous

来源：ChemMedChem, 2014, 9(11): 2449-2453.

DOI：10.1002/cmdc.201402230

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

Two bicyclic peptides composed of tryptophan and arginine residues were synthesized from monocyclic peptide building blocks and evaluated as cellular delivery agents. [W(5)G]-(triazole)-[KR5] and [W5E]-(-Ala)-[KR5] containing triazole and -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 [R-5] 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]-(-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 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.

• 出版日期2014-11