title: Amphiphilic bicyclic peptides as cellular delivery agents.
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.
authors.affiliation: Department of Biomedical & Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Kingston, RI 02881 (USA).
authors.forename: Donghoon
authors.initials: D
authors.lastname: Oh
authors.forename: Shaban Anwar
authors.initials: SA
authors.lastname: Darwish
authors.forename: Amir Nasrolahi
authors.initials: AN
authors.lastname: Shirazi
authors.forename: Rakesh Kumar
authors.initials: RK
authors.lastname: Tiwari
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000633:toxicity; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005434:Flow Cytometry; D019793:Fluorescein / Q000737:chemistry; D006801:Humans; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D010456:Peptides, Cyclic; D004317:Doxorubicin; D019793:Fluorescein
keywords: amphiphiles; bicyclic peptides; cell-penetrating; drug delivery; endocytosis