Cysteine and arginine-rich peptides as molecular carriers

Abstract

A number of linear and cyclic peptides containing alternative arginine and cysteine residues, namely linear (CR)3, linear (CR)4, linear (CR)5, cyclic [CR]4, and cyclic [CR]5, were synthesized. The peptides were evaluated for their ability to deliver two molecular cargos, fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F'-GpYEEI) and fluorescence-labeled lamivudine (F'-3TC), intracellularly in human leukemia cancer (CCRF-CEM) cells. We investigated the role of cyclization and the number of amino acids in improving the transporting ability of the peptides. The flow cytometry studies suggested that the synthesized peptides were able to work efficiently as transporters for both cargos. Among all compounds, cyclic [CR]4 was found to be the most efficient peptide in transporting the cargo into cells. For instance, the cellular uptake of F'-3TC (5μM) and F'-GpYEEI (5μM) was enhanced by 16- and 20-fold, respectively, in the presence of cyclic [CR]4 compared to that of the parent compound alone. The mechanism of F'-GpYEEI uptake by cells was found to be energy-independent. The results showed that the number of amino acids and their cyclic nature can impact the efficiency of the peptide in transporting the molecular cargos.

Development of iRGD-Modified Peptide Carriers for Suicide Gene Therapy of Uterine Leiomyoma

“…Arginine-rich peptides belonging to cationic cell penetrating peptides (CPPs) are effective for in vitro and in vivo gene delivery [23][24][25]. Previous studies have shown that CPPs crosslinked by disulfide bonds promote efficient gene transfection and low cytotoxicity, due to the fact that disulfide bonds can be split by intracellular reducing compounds as glutathione for to release DNA [26][27][28]. Importantly, cysteine-flanked cross-linking peptides (CLP) have a higher charge density, which increases their ability to condense DNA [29].…”

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

“…It was expected that the attachment of fatty acids or hydrophobic residues to a cationic CPPs will increase the peptide′s hydrophobicity. Hydrophobicity enhances the interactions with the cell membrane phospholipids leading to increased cellular uptake, and/or modulating both activity and selectivity [ 25 , 27 , 28 , 29 ]. Thus, a library of fatty acyl-(HR) 4 peptides were synthesized using Wang resin as the solid support as shown in Scheme 2 .…”

“…In our previous studies, we explored the combination of attaching different hydrophobic amino acids and charged residues with or without fatty acids to get homochiral CPPs as molecular transporters named [WR] 4 and [WR] 5 [ 2 , 20 , 21 , 22 , 23 , 24 ]. Also, a further effort led to the development of new series of peptides named [CR] 4 and [CR] 5 which contains cysteine and arginine residues that showed an efficient molecular transporter’s property for a diverse group of bioactive molecules [ 25 ]. In the frame work of developing unique CPPs to explore their application of molecular transporter properties and the targeting of cargos to cancer cells, we aimed to develop novel CPPs with alternating arginine and histidine amino acids to evaluate their ability to translocate various biomolecular cargoes of different molecular size and hydrophobic nature to the cancer cells.…”

Cyclization of a cell‐penetrating peptide via click‐chemistry increases proteolytic resistance and improves drug delivery

“…In previous studies, peptide cyclization was demonstrated to be an effective strategy for enhancing cellular uptake and promoting endosomal escape . This phenomenon was mostly applied to arginine‐rich CPPs arguing that static presentation of the arginine residues would lead to better interaction with negatively charged head groups at the outer membrane surface .…”