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Open AccessArticle

Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization

1
Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA
2
Chemistry Department, Faculty of Science, Chemistry department, Menoufia University, Shebin El-Koam 51132, Egypt
3
Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Silvia Panzavolta and Luisa Stella Dolci
Molecules 2020, 25(11), 2581; https://doi.org/10.3390/molecules25112581
Received: 14 April 2020 / Revised: 27 May 2020 / Accepted: 27 May 2020 / Published: 2 June 2020
(This article belongs to the Special Issue Applications of Materials in Drug Delivery)
We have previously reported cyclic cell-penetrating peptides [WR]5 and [WR]4 as molecular transporters. To optimize further the utility of our developed peptides for targeted therapy in cancer cells using the redox condition, we designed a new generation of peptides and evaluated their cytotoxicity as well as uptake behavior against different cancer cell lines. Thus, cyclic [C(WR)xC] and linear counterparts (C(WR)xC), where x = 4–5, were synthesized using Fmoc/tBu solid-phase peptide synthesis, purified, and characterized. The compounds did not show any significant cytotoxicity (at 25 µM) against ovarian (SK-OV-3), leukemia (CCRF-CEM), gastric adenocarcinoma (CRL-1739), breast carcinoma (MDA-MB-231), and normal kidney (LLCPK) cells after 24 and 72 h incubation. Both cyclic [C(WR)5C] and linear (C(WR)5C) demonstrated comparable molecular transporter properties versus [WR]5 in the delivery of a phosphopeptide (F′-GpYEEI) in CCRF-CEM cells. The uptake of F′-GpYEEI in the presence of 1,4-dithiothreitol (DTT) as the reducing agent was significantly improved in case of l(C(WR)5C), while it was not changed by [C(WR)5C]. Fluorescence microscopy also demonstrated a significant uptake of F′-GpYEEI in the presence of l(C(WR)5C). Cyclic [C(WR)5C] improved the uptake of the fluorescent-labeled anti-HIV drugs F′-d4T, F′-3TC, and F′-FTC by 3.0–4.9-fold. These data indicate that both [C(WR)5C] and linear (C(WR)5C) peptides can act as molecular transporters. View Full-Text
Keywords: cell-penetrating peptide; cancer; cytotoxicity; cellular uptake; disulfide bridge; drug delivery; phosphopeptide cell-penetrating peptide; cancer; cytotoxicity; cellular uptake; disulfide bridge; drug delivery; phosphopeptide
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MDPI and ACS Style

Mohammed, E.H.M.; Mandal, D.; Mozaffari, S.; Abdel-Hamied Zahran, M.; Mostafa Osman, A.; Kumar Tiwari, R.; Parang, K. Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization. Molecules 2020, 25, 2581.

AMA Style

Mohammed EHM, Mandal D, Mozaffari S, Abdel-Hamied Zahran M, Mostafa Osman A, Kumar Tiwari R, Parang K. Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization. Molecules. 2020; 25(11):2581.

Chicago/Turabian Style

Mohammed, Eman H.M.; Mandal, Dindyal; Mozaffari, Saghar; Abdel-Hamied Zahran, Magdy; Mostafa Osman, Amany; Kumar Tiwari, Rakesh; Parang, Keykavous. 2020. "Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization" Molecules 25, no. 11: 2581.

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