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Molecules 2018, 23(7), 1590; https://doi.org/10.3390/molecules23071590

Design, Synthesis, and Evaluation of Homochiral Peptides Containing Arginine and Histidine as Molecular Transporters

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
Cellulose and Paper Department, National Research Center, Dokki, Cairo 12622, Egypt
*
Author to whom correspondence should be addressed.
Received: 3 May 2018 / Revised: 20 June 2018 / Accepted: 26 June 2018 / Published: 29 June 2018
(This article belongs to the Special Issue Cell-Penetrating Peptides (CPPs))
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Abstract

Linear (HR)n and cyclic [HR]n peptides (n = 4,5) containing alternate arginine and histidine residues were synthesized. The peptides showed 0–15% cytotoxicity at 5–100 µM in human ovarian adenocarcinoma (SK-OV-3) cells while they exhibited 0–12% 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 µM concentration; however, at higher concentration (100 µM), 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 µM and C20-(HR)4 showed mild toxicity at 10 µM, 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′-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. View Full-Text
Keywords: anticancer drugs; fatty acyl peptides; histidine; phosphopeptides; molecular transporters; cytotoxicity anticancer drugs; fatty acyl peptides; histidine; phosphopeptides; molecular transporters; cytotoxicity
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El-Sayed, N.S.; Miyake, T.; Shirazi, A.N.; Park, S.E.; Clark, J.; Buchholz, S.; Parang, K.; Tiwari, R. Design, Synthesis, and Evaluation of Homochiral Peptides Containing Arginine and Histidine as Molecular Transporters. Molecules 2018, 23, 1590.

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