Amphiphilic cyclic cell-penetrating peptides as drug delivery vehicles and antimicrobial peptides

Donghoon Oh, University of Rhode Island

Abstract

Cell membrane is a barrier to be overcome for efficient delivery of therapeutics into a target site in cytoplasm or nucleus. The hydrophobic phospholipids are major components of the cell membrane that obstruct the transportation of therapeutics. Thus, various delivery systems, such as liposomes, nanoparticles and viral vectors, have been developed to transfer small molecules, peptides, proteins, and oligonucleotides across the membrane. ^ Negatively charged phosphopeptides, oligonucleotides, and siRNAs have emerged as potential therapeutic agents. Phosphopeptides mimic phosphoproteins, which give on/off signal to many enzymes through interactions with protein kinases. For example, phosphopeptide pTyr-Glu-Glu-Ile (pYEEI) is an optimal peptide ligand for binding to the Src tyrosine kinase SH2 domain. Oligonucleotides have been introduced as antisense drugs to inhibit the translation of mRNA that transfers the coding information from genes. Small interfering RNA (siRNA)-based therapy has been also spotlighted since the discovery of RNA interference (RNAi) phenomenon. However, the cellular delivery of phosphopeptides, oligonucleotides, and siRNAs is a major obstacle despite many advantages of these compounds. Phosphopeptides contain negatively charged phosphate group, and/or negatively charged amino acids, such as glutamic acid or aspartic acid, in their sequences. Oligonucleotides and siRNAs are polymers composed of nucleosides, which are connected through negatively charged phosphodiester groups. These negatively charged molecules are hard to enter cancer cells by diffusion because cancer cell membranes are composed of negatively charged lipids. In addition, when a naked siRNA is administered in vivo, it does not show efficient cellular uptake in most mammalian cells and is quickly disappeared in the blood. Thus, developing carriers to improve the cellular uptake delivery of negatively charged cell-impermeable compounds has become a subject of major interest. Novel strategies are urgently needed to circumvent the problems associated with the delivery of these compounds. ^ Cell-penetrating peptides (CPPs) have become one of the emerging vehicles for delivery of cargo drugs. CPPs are short hydrophilic or amphiphilic peptides that have plenty of positively charged amino acids, such as lysine or arginine, which can penetrate cell membranes. CPP-drug conjugates have been reported to help the cellular uptake of some drugs. Alternatively, they have been used as non-covalent drug delivery systems. ^ CPPs have been investigated for improving the intracellular delivery of negatively-charged molecules. By physical interaction between positive charges in CPPs and negative charges in phosphopeptides, oligonucleotides, and siRNAs, the cell penetration could be improved. Among many CPPs, arginine-rich peptides have been the subject of major focus because it has been known that the guanidine group of arginine side chain shows better interaction with the negatively charged phospholipid in the cell membrane. Tryptophan is also a key amino acid found in CPPs that enhances the interaction of peptides with lipids in the cell membrane. ^ Parang's laboratory has previously shown that monocyclic CPPs containing alternative arginine and tryptophan have potential applications for drug delivery. Cyclic peptides have several benefits compared to linear peptides, such as stability against proteolytic enzymes and rigidness of structure. The rigidity of the structure can enhance the binding affinity of ligands toward receptors by reducing the freedom of possible structural conformations. Cyclic peptides are also present in nature and have been developed as therapeutics. Cyclosporin, gramicin S, polymoxin B, and daptomycin are well-known examples of cyclic peptides. Parang's laboratory designed amphiphilic cyclic CPPs containing alternative tryptophan and argininge residues as the positively charged and hydrophobic residues, respectively. The peptides were efficient in improving the cellular delivery of anticancer and antiviral drugs. ^ In this dissertation, we designed novel classes of amphiphilic cyclic peptides for improving the intracellular delivery of cell-impermeable phosphopeptides, and their antimicrobial activities were investigated. The hypothesis of this dissertation is that amphiphilic cyclic peptides, having positively charged arginines on one side of structures and hydrophobic tryptophan (or fatty acid) on the other side, can enhance intracellular drug delivery and/or act as antimicrobial agents having synergy with other antibiotics. (Abstract shortened by UMI.) ^

Subject Area

Chemistry, Molecular|Health Sciences, Pharmacy

Recommended Citation

Donghoon Oh, "Amphiphilic cyclic cell-penetrating peptides as drug delivery vehicles and antimicrobial peptides" (2014). Dissertations and Master's Theses (Campus Access). Paper AAI3619471.
http://digitalcommons.uri.edu/dissertations/AAI3619471

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