Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization
We have previously reported cyclic cell-penetrating peptides [WR]<sub>5</sub> and [WR]<sub>4</sub> 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...
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MDPI AG
2020-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/11/2581 |
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| author | Eman H. M. Mohammed Dindyal Mandal Saghar Mozaffari Magdy Abdel-Hamied Zahran Amany Mostafa Osman Rakesh Kumar Tiwari Keykavous Parang |
| author_facet | Eman H. M. Mohammed Dindyal Mandal Saghar Mozaffari Magdy Abdel-Hamied Zahran Amany Mostafa Osman Rakesh Kumar Tiwari Keykavous Parang |
| author_sort | Eman H. M. Mohammed |
| collection | DOAJ |
| description | We have previously reported cyclic cell-penetrating peptides [WR]<sub>5</sub> and [WR]<sub>4</sub> 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)<sub>x</sub>C] and linear counterparts (C(WR)<sub>x</sub>C), where x = 4–5, were synthesized using Fmoc/<i>t</i>Bu 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)<sub>5</sub>C] and linear (C(WR)<sub>5</sub>C) demonstrated comparable molecular transporter properties versus [WR]<sub>5</sub> 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)<sub>5</sub>C), while it was not changed by [C(WR)<sub>5</sub>C]. Fluorescence microscopy also demonstrated a significant uptake of F′-GpYEEI in the presence of l(C(WR)<sub>5</sub>C). Cyclic [C(WR)<sub>5</sub>C] 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)<sub>5</sub>C] and linear (C(WR)<sub>5</sub>C) peptides can act as molecular transporters. |
| first_indexed | 2024-03-10T19:25:22Z |
| format | Article |
| id | doaj.art-2216796db19b4799b949af17d8146ec0 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T19:25:22Z |
| publishDate | 2020-06-01 |
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| spelling | doaj.art-2216796db19b4799b949af17d8146ec02023-11-20T02:36:11ZengMDPI AGMolecules1420-30492020-06-012511258110.3390/molecules25112581Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide CyclizationEman H. M. Mohammed0Dindyal Mandal1Saghar Mozaffari2Magdy Abdel-Hamied Zahran3Amany Mostafa Osman4Rakesh Kumar Tiwari5Keykavous Parang6Center 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, USACenter 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, USACenter 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, USAChemistry Department, Faculty of Science, Chemistry department, Menoufia University, Shebin El-Koam 51132, EgyptChemistry Department, Faculty of Science, Chemistry department, Menoufia University, Shebin El-Koam 51132, EgyptCenter 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, USACenter 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, USAWe have previously reported cyclic cell-penetrating peptides [WR]<sub>5</sub> and [WR]<sub>4</sub> 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)<sub>x</sub>C] and linear counterparts (C(WR)<sub>x</sub>C), where x = 4–5, were synthesized using Fmoc/<i>t</i>Bu 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)<sub>5</sub>C] and linear (C(WR)<sub>5</sub>C) demonstrated comparable molecular transporter properties versus [WR]<sub>5</sub> 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)<sub>5</sub>C), while it was not changed by [C(WR)<sub>5</sub>C]. Fluorescence microscopy also demonstrated a significant uptake of F′-GpYEEI in the presence of l(C(WR)<sub>5</sub>C). Cyclic [C(WR)<sub>5</sub>C] 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)<sub>5</sub>C] and linear (C(WR)<sub>5</sub>C) peptides can act as molecular transporters.https://www.mdpi.com/1420-3049/25/11/2581cell-penetrating peptidecancercytotoxicitycellular uptakedisulfide bridgedrug delivery |
| spellingShingle | Eman H. M. Mohammed Dindyal Mandal Saghar Mozaffari Magdy Abdel-Hamied Zahran Amany Mostafa Osman Rakesh Kumar Tiwari Keykavous Parang Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization Molecules cell-penetrating peptide cancer cytotoxicity cellular uptake disulfide bridge drug delivery |
| title | Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization |
| title_full | Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization |
| title_fullStr | Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization |
| title_full_unstemmed | Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization |
| title_short | Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization |
| title_sort | comparative molecular transporter properties of cyclic peptides containing tryptophan and arginine residues formed through disulfide cyclization |
| topic | cell-penetrating peptide cancer cytotoxicity cellular uptake disulfide bridge drug delivery |
| url | https://www.mdpi.com/1420-3049/25/11/2581 |
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