Design, Synthesis, and Evaluation of Homochiral Peptides Containing Arginine and Histidine as Molecular Transporters
| Autor: | Shang Eun Park, Jimmy Clark, Stephani Buchholz, Keykavous Parang, Taryn Miyake, Rakesh Tiwari, Amir Nasrolahi Shirazi, Naglaa Salem El-Sayed |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Arginine Cell Survival Cell Pharmaceutical Science Peptide Antineoplastic Agents Cell-Penetrating Peptides 01 natural sciences Peptides Cyclic Article Analytical Chemistry lcsh:QD241-441 Cell membrane 03 medical and health sciences Drug Delivery Systems lcsh:Organic chemistry Cell Line Tumor Drug Discovery medicine Humans molecular transporters Physical and Theoretical Chemistry Cytotoxicity Histidine Cell Proliferation chemistry.chemical_classification 010405 organic chemistry Phosphopeptide Organic Chemistry Biological Transport histidine fatty acyl peptides 0104 chemical sciences anticancer drugs 030104 developmental biology medicine.anatomical_structure chemistry Biochemistry Chemistry (miscellaneous) Cell culture phosphopeptides Molecular Medicine cytotoxicity lipids (amino acids peptides and proteins) Peptides |
| Zdroj: | Molecules Volume 23 Issue 7 Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry Molecules, Vol 23, Iss 7, p 1590 (2018) |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules23071590 |
| Popis: | Linear (HR)n and cyclic [HR]n peptides (n = 4,5) containing alternate arginine and histidine residues were synthesized. The peptides showed 0&ndash 15% cytotoxicity at 5&ndash 100 µ M in human ovarian adenocarcinoma (SK-OV-3) cells while they exhibited 0&ndash 12% toxicity in human leukemia cancer cell line (CCRF-CEM). Among all peptides, cyclic [HR]4 peptide was able to improve the delivery of a cell impermeable fluorescence-labeled phosphopeptide by two-fold. Fatty acids of different alkyl chain length were attached at the N-terminal of the linear peptide (HR)4 to improve the molecular transporter property. Addition of fatty acyl chains was expected to help with the permeation of the peptides through the cell membrane. Thus, we synthesized seven fatty acyl derivatives of the linear (HR)4 peptide. The peptides were synthesized using Fmoc/tBu solid phase peptide chemistry, purified by reverse-phase high-performance liquid chromatography (RP-HPLC) and characterized by matrix-assisted laser desorption/ionization (MALDI) spectrometry. The fatty acyl peptides containing C8, C12, C14, and C18 alkyl chain did not show cytotoxicity on SK-OV-3 or CCRF-CEM cell lines up to 50 µ M concentration however, at higher concentration (100 µ M), they showed mild cytotoxicity. For example, C16-(HR)4 was also found to reduce the proliferation of SK-OV-3 cells by 11% at 50 µ M and C20-(HR)4 showed mild toxicity at 10 µ M, reducing the proliferation of SK-OV-3 cells by 21%. Increase in the length of alkyl chain showed cytotoxicity to the cell lines. C20-(HR)4 peptide showed better efficiency in translocation of F&prime GpYEEI to SK-OV-3 than the phosphopeptide alone. Further investigation of C20-(HR)4 peptide efficacy showed that the peptide could deliver doxorubicin and epirubicin into SK-OV-3 and also improved the drug antiproliferative ability. These studies provided insights into understanding the structural requirements for optimal cellular delivery of the fatty acyl-(HR)4 peptide conjugates. |
| Databáze: | OpenAIRE |
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