Amphiphilic bicyclic peptides as cellular delivery agents

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

doi:10.1002/cmdc.201402230

Amphiphilic bicyclic peptides as cellular delivery agents

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

Research output: Contribution to journal › Article › peer-review

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)
Pages (from-to)	2449-2453
Number of pages	5
Journal	ChemMedChem
Volume	9
Issue number	11
DOIs	https://doi.org/10.1002/cmdc.201402230
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)

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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.",

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author = "Donghoon Oh and Darwish, {Shaban Anwar} and Shirazi, {Amir Nasrolahi} and Tiwari, {Rakesh Kumar} and Keykavous Parang",

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AU - Oh, Donghoon

AU - Darwish, Shaban Anwar

AU - Shirazi, Amir Nasrolahi

AU - Tiwari, Rakesh Kumar

AU - Parang, Keykavous

PY - 2014/11/1

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AB - 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.

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Amphiphilic bicyclic peptides as cellular delivery agents

Abstract

Keywords

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