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

Authors

Eman H. M. Mohammed, Chapman UniversityFollow
Dindyal Mandal, Chapman UniversityFollow
Saghar Mozaffari, Chapman UniversityFollow
Magdy Abdel-Hamied Zahran, Menoufia UniversityFollow
Amany Mostafa Osman, Menoufia UniversityFollow
Rakesh Kumar Tiwari, Chapman UniversityFollow
Keykavous Parang, Chapman UniversityFollow

Document Type

Article

Publication Date

6-2-2020

Abstract

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.

Comments

This article was originally published in Molecules, volume 25, issue 11, in 2020. https://doi.org/10.3390/molecules25112581

Recommended Citation

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. https://doi.org/10.3390/molecules25112581

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