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Cell-Penetrating Peptides

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 September 2015) | Viewed by 75824

Special Issue Editors

Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND 58108-6050, USA
Interests: mechanistic studies for developing and testing novel delivery technologies to deliver biotechnologically derived molecules (e.g., peptide, protein, and gene); gene delivery to prevent and treat neurodegenerative disorders, using nanotechnology; delivery of anticancer drugs to the brain for the treatment of brain tumors using bi-ligand (transferrin and cell-penetrating peptides) tethered liposomes; synthesis and characterization of biomaterials for gene and protein delivery for the treatment of diabetes, osteoporosis, and neurodegenerative diseases; fatty acid/amino acid and cell-penetrating peptide-grafted chitosan-based nanomicelles for the delivery of pDNA encoding IL-4 and IL-10 for the prevention of type 1 diabetes; cationic nanomicelles for the delivery of DNA vaccines
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Special Issue Information

Dear Colleagues,

The hydrophobic nature of cell membranes prevents the cellular internalization of exogenous molecules, including different bioactive molecules such as proteins, peptides, and oligonucleotides as well as therapeutics. Discovery of a protein transcription domain that possesses the ability to cross the cell membrane, cell-penetrating peptides (CPPs), has led to a paradigm shift for intracellular delivery of hydrophilic molecules. Since its discovery in the late 1980s, CPPs have been extensively evaluated to assist intracellular delivery of covalently or non-covalently conjugated bioactive cargos, including DNA, siRNA, peptide, protein, liposomes, micelles, nanoparticles, etc. Even though the field of CPPs has advanced rapidly,  there is limited data on the mechanism of cellular entry of CPPs, and it remains as a subject of controversy in the literature. Hence, this Special Issue will focus on the recent advancement of CPPs as a vector for drug and gene delivery, as well as a detailed mechanistic evaluation of CPPs-mediated transmembrane transportation.

Prof. Dr. Jagdish Singh
Dr. Buddhadev Layek
Guest Editors

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Keywords

  • cell penetrating peptide
  • drug delivery
  • gene delivery
  • endocytosis
  • transport mechanism

Published Papers (9 papers)

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Research

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2177 KiB  
Article
Biodistribution, Stability, and Blood Distribution of the Cell Penetrating Peptide Maurocalcine in Mice
by Pascale Perret, Mitra Ahmadi, Laurent Riou, Sandrine Bacot, Julien Pecher, Cathy Poillot, Alexis Broisat, Catherine Ghezzi and Michel De Waard
Int. J. Mol. Sci. 2015, 16(11), 27730-27740; https://doi.org/10.3390/ijms161126054 - 19 Nov 2015
Cited by 13 | Viewed by 5169
Abstract
Maurocalcine (MCa) is the first natural cell penetrating peptide to be discovered in animal venom. In addition to the fact that it represents a potent vector for the cell penetration of structurally diverse therapeutic compounds, MCa also displays several distinguishing features that make [...] Read more.
Maurocalcine (MCa) is the first natural cell penetrating peptide to be discovered in animal venom. In addition to the fact that it represents a potent vector for the cell penetration of structurally diverse therapeutic compounds, MCa also displays several distinguishing features that make it a potential peptide of choice for clinical and biotechnological applications. The aim of the present study was to gain new information about the properties of MCa in vivo in order to delineate the future potential applications of this vector. For this purpose, two analogues of this peptide with (Tyr-MCa) and without (Lin-Tyr-MCa) disulfide bridges were synthesized, radiolabeled with 125I, and their in vitro stabilities were first evaluated in mouse blood. The results indicated that 125I-Tyr-MCa was stable in vitro and that the disulfide bridges conferred a competitive advantage for the stability of peptide. Following in vivo injection in mice, 125I-Tyr-MCa targeted peripheral organs with interesting quantitative differences and the main route of peptide elimination was renal. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides)
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1273 KiB  
Article
Cell-Penetrating Ability of Peptide Hormones: Key Role of Glycosaminoglycans Clustering
by Armelle Tchoumi Neree, Phuong Trang Nguyen and Steve Bourgault
Int. J. Mol. Sci. 2015, 16(11), 27391-27400; https://doi.org/10.3390/ijms161126025 - 16 Nov 2015
Cited by 7 | Viewed by 5119
Abstract
Over the last two decades, the potential usage of cell-penetrating peptides (CPPs) for the intracellular delivery of various molecules has prompted the identification of novel peptidic identities. However, cytotoxic effects and unpredicted immunological responses have often limited the use of various CPP sequences [...] Read more.
Over the last two decades, the potential usage of cell-penetrating peptides (CPPs) for the intracellular delivery of various molecules has prompted the identification of novel peptidic identities. However, cytotoxic effects and unpredicted immunological responses have often limited the use of various CPP sequences in the clinic. To overcome these issues, the usage of endogenous peptides appears as an appropriate alternative approach. The hormone pituitary adenylate-cyclase-activating polypeptide (PACAP38) has been recently identified as a novel and very efficient CPP. This 38-residue polycationic peptide is a member of the secretin/glucagon/growth hormone-releasing hormone (GHRH) superfamily, with which PACAP38 shares high structural and conformational homologies. In this study, we evaluated the cell-penetrating ability of cationic peptide hormones in the context of the expression of cell surface glycosaminoglycans (GAGs). Our results indicated that among all peptides evaluated, PACAP38 was unique for its potent efficiency of cellular uptake. Interestingly, the abilities of the peptides to reach the intracellular space did not correlate with their binding affinities to sulfated GAGs, but rather to their capacity to clustered heparin in vitro. This study demonstrates that the uptake efficiency of a given cationic CPP does not necessarily correlate with its affinity to sulfated GAGs and that its ability to cluster GAGs should be considered for the identification of novel peptidic sequences with potent cellular penetrating properties. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides)
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Review

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216 KiB  
Review
Intracellular Delivery of Proteins with Cell-Penetrating Peptides for Therapeutic Uses in Human Disease
by Ana Dinca, Wei-Ming Chien and Michael T. Chin
Int. J. Mol. Sci. 2016, 17(2), 263; https://doi.org/10.3390/ijms17020263 - 22 Feb 2016
Cited by 119 | Viewed by 9125
Abstract
Protein therapy exhibits several advantages over small molecule drugs and is increasingly being developed for the treatment of disorders ranging from single enzyme deficiencies to cancer. Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the [...] Read more.
Protein therapy exhibits several advantages over small molecule drugs and is increasingly being developed for the treatment of disorders ranging from single enzyme deficiencies to cancer. Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered proteins. Although the molecular mechanisms of uptake are not firmly established, CPPs have been empirically shown to promote uptake of various molecules, including large proteins over 100 kiloDaltons (kDa). Recombinant proteins that include a CPP tag to promote intracellular delivery show promise as therapeutic agents with encouraging success rates in both animal and human trials. This review highlights recent advances in protein-CPP therapy and discusses optimization strategies and potential detrimental effects. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides)
620 KiB  
Review
Applications and Challenges for Use of Cell-Penetrating Peptides as Delivery Vectors for Peptide and Protein Cargos
by Mie Kristensen, Ditlev Birch and Hanne Mørck Nielsen
Int. J. Mol. Sci. 2016, 17(2), 185; https://doi.org/10.3390/ijms17020185 - 30 Jan 2016
Cited by 219 | Viewed by 12331
Abstract
The hydrophilic nature of peptides and proteins renders them impermeable to cell membranes. Thus, in order to successfully deliver peptide and protein-based therapeutics across the plasma membrane or epithelial and endothelial barriers, a permeation enhancing strategy must be employed. Cell-penetrating peptides (CPPs) constitute [...] Read more.
The hydrophilic nature of peptides and proteins renders them impermeable to cell membranes. Thus, in order to successfully deliver peptide and protein-based therapeutics across the plasma membrane or epithelial and endothelial barriers, a permeation enhancing strategy must be employed. Cell-penetrating peptides (CPPs) constitute a promising tool and have shown applications for peptide and protein delivery into cells as well as across various epithelia and the blood-brain barrier (BBB). CPP-mediated delivery of peptides and proteins may be pursued via covalent conjugation of the CPP to the cargo peptide or protein or via physical complexation obtained by simple bulk-mixing of the CPP with its cargo. Both approaches have their pros and cons, and which is the better choice likely relates to the physicochemical properties of the CPP and its cargo as well as the route of administration, the specific barrier and the target cell. Besides the physical barrier, a metabolic barrier must be taken into consideration when applying peptide-based delivery vectors, such as the CPPs, and stability-enhancing strategies are commonly employed to prolong the CPP half-life. The mechanisms by which CPPs translocate cell membranes are believed to involve both endocytosis and direct translocation, but are still widely investigated and discussed. The fact that multiple factors influence the mechanisms responsible for cellular CPP internalization and the lack of sensitive methods for detection of the CPP, and in some cases the cargo, further complicates the design and conduction of conclusive mechanistic studies. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides)
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973 KiB  
Review
Cell Penetrating Peptide Conjugated Chitosan for Enhanced Delivery of Nucleic Acid
by Buddhadev Layek, Lindsey Lipp and Jagdish Singh
Int. J. Mol. Sci. 2015, 16(12), 28912-28930; https://doi.org/10.3390/ijms161226142 - 04 Dec 2015
Cited by 67 | Viewed by 15195
Abstract
Gene therapy is an emerging therapeutic strategy for the cure or treatment of a spectrum of genetic disorders. Nevertheless, advances in gene therapy are immensely reliant upon design of an efficient gene carrier that can deliver genetic cargoes into the desired cell populations. [...] Read more.
Gene therapy is an emerging therapeutic strategy for the cure or treatment of a spectrum of genetic disorders. Nevertheless, advances in gene therapy are immensely reliant upon design of an efficient gene carrier that can deliver genetic cargoes into the desired cell populations. Among various nonviral gene delivery systems, chitosan-based carriers have gained increasing attention because of their high cationic charge density, excellent biocompatibility, nearly nonexistent cytotoxicity, negligible immune response, and ideal ability to undergo chemical conjugation. However, a major shortcoming of chitosan-based carriers is their poor cellular uptake, leading to inadequate transfection efficiency. The intrinsic feature of cell penetrating peptides (CPPs) for transporting diverse cargoes into multiple cell and tissue types in a safe manner suggests that they can be conjugated to chitosan for improving its transfection efficiency. In this review, we briefly discuss CPPs and their classification, and also the major mechanisms contributing to the cellular uptake of CPPs and cargo conjugates. We also discuss immense improvements for the delivery of nucleic acids using CPP-conjugated chitosan-based carriers with special emphasis on plasmid DNA and small interfering RNA. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides)
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366 KiB  
Review
Therapeutic Potential of Cell Penetrating Peptides (CPPs) and Cationic Polymers for Chronic Hepatitis B
by Bénédicte Ndeboko, Guy Joseph Lemamy, Peter. E Nielsen and Lucyna Cova
Int. J. Mol. Sci. 2015, 16(12), 28230-28241; https://doi.org/10.3390/ijms161226094 - 27 Nov 2015
Cited by 21 | Viewed by 5393
Abstract
Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. Because current anti-HBV treatments are only virostatic, there is an urgent need for development of alternative antiviral approaches. In this context, cell-penetrating peptides (CPPs) and cationic polymers, such as chitosan (CS), [...] Read more.
Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. Because current anti-HBV treatments are only virostatic, there is an urgent need for development of alternative antiviral approaches. In this context, cell-penetrating peptides (CPPs) and cationic polymers, such as chitosan (CS), appear of particular interest as nonviral vectors due to their capacity to facilitate cellular delivery of bioactive cargoes including peptide nucleic acids (PNAs) or DNA vaccines. We have investigated the ability of a PNA conjugated to different CPPs to inhibit the replication of duck hepatitis B virus (DHBV), a reference model for human HBV infection. The in vivo administration of PNA-CPP conjugates to neonatal ducklings showed that they reached the liver and inhibited DHBV replication. Interestingly, our results indicated also that a modified CPP (CatLip) alone, in the absence of its PNA cargo, was able to drastically inhibit late stages of DHBV replication. In the mouse model, conjugation of HBV DNA vaccine to modified CS (Man-CS-Phe) improved cellular and humoral responses to plasmid-encoded antigen. Moreover, other systems for gene delivery were investigated including CPP-modified CS and cationic nanoparticles. The results showed that these nonviral vectors considerably increased plasmid DNA uptake and expression. Collectively promising results obtained in preclinical studies suggest the usefulness of these safe delivery systems for the development of novel therapeutics against chronic hepatitis B. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides)
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1220 KiB  
Review
Cell-Penetrating Peptide as a Means of Directing the Differentiation of Induced-Pluripotent Stem Cells
by Taku Kaitsuka and Kazuhito Tomizawa
Int. J. Mol. Sci. 2015, 16(11), 26667-26676; https://doi.org/10.3390/ijms161125986 - 06 Nov 2015
Cited by 20 | Viewed by 6325
Abstract
Protein transduction using cell-penetrating peptides (CPPs) is useful for the delivery of large protein molecules, including some transcription factors. This method is safer than gene transfection methods with a viral vector because there is no risk of genomic integration of the exogenous DNA. [...] Read more.
Protein transduction using cell-penetrating peptides (CPPs) is useful for the delivery of large protein molecules, including some transcription factors. This method is safer than gene transfection methods with a viral vector because there is no risk of genomic integration of the exogenous DNA. Recently, this method was reported as a means for the induction of induced pluripotent stem (iPS) cells, directing the differentiation into specific cell types and supporting gene editing/correction. Furthermore, we developed a direct differentiation method to obtain a pancreatic lineage from mouse and human pluripotent stem cells via the protein transduction of three transcription factors, Pdx1, NeuroD, and MafA. Here, we discuss the possibility of using CPPs as a means of directing the differentiation of iPS cells and other stem cell technologies. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides)
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753 KiB  
Review
Membranotropic Cell Penetrating Peptides: The Outstanding Journey
by Annarita Falanga, Massimiliano Galdiero and Stefania Galdiero
Int. J. Mol. Sci. 2015, 16(10), 25323-25337; https://doi.org/10.3390/ijms161025323 - 23 Oct 2015
Cited by 47 | Viewed by 5917
Abstract
The membrane bilayer delimits the interior of individual cells and provides them with the ability to survive and function properly. However, the crossing of cellular membranes constitutes the principal impediment to gaining entry into cells, and the potential therapeutic application of many drugs [...] Read more.
The membrane bilayer delimits the interior of individual cells and provides them with the ability to survive and function properly. However, the crossing of cellular membranes constitutes the principal impediment to gaining entry into cells, and the potential therapeutic application of many drugs is predominantly dependent on the development of delivery tools that should take the drug to target cells selectively and efficiently with only minimal toxicity. Cell-penetrating peptides are short and basic peptides are widely used due to their ability to deliver a cargo across the membrane both in vitro and in vivo. It is widely accepted that their uptake mechanism involves mainly the endocytic pathway, the drug is catched inside endosomes and lysosomes, and only a small quantity is able to reach the intracellular target. In this wide-ranging scenario, a fascinating novel hypothesis is that membranotropic peptides that efficiently cross biological membranes, promote lipid-membrane reorganizing processes and cause a local and temporary destabilization and reorganization of the membrane bilayer, may also be able to enter cells circumventing the endosomal entrapment; in particular, by either favoring the escape from the endosome or by direct translocation. This review summarizes current data on membranotropic peptides for drug delivery. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides)
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1468 KiB  
Review
Intracellular Delivery of Molecular Cargo Using Cell-Penetrating Peptides and the Combination Strategies
by Hua Li, Tung Yu Tsui and Wenxue Ma
Int. J. Mol. Sci. 2015, 16(8), 19518-19536; https://doi.org/10.3390/ijms160819518 - 18 Aug 2015
Cited by 49 | Viewed by 10576
Abstract
Cell-penetrating peptides (CPPs) can cross cellular membranes in a non-toxic fashion, improving the intracellular delivery of various molecular cargos such as nanoparticles, small molecules and plasmid DNA. Because CPPs provide a safe, efficient, and non-invasive mode of transport for various cargos into cells, [...] Read more.
Cell-penetrating peptides (CPPs) can cross cellular membranes in a non-toxic fashion, improving the intracellular delivery of various molecular cargos such as nanoparticles, small molecules and plasmid DNA. Because CPPs provide a safe, efficient, and non-invasive mode of transport for various cargos into cells, they have been developed as vectors for the delivery of genetic and biologic products in recent years. Most common CPPs are positively charged peptides. While delivering negatively charged molecules (e.g., nucleic acids) to target cells, the internalization efficiency of CPPs is reduced and inhibited because the cationic charges on the CPPs are neutralized through the covering of CPPs by cargos on the structure. Even under these circumstances, the CPPs can still be non-covalently complexed with the negatively charged molecules. To address this issue, combination strategies of CPPs with other typical carriers provide a promising and novel delivery system. This review summarizes the latest research work in using CPPs combined with molecular cargos including liposomes, polymers, cationic peptides, nanoparticles, adeno-associated virus (AAV) and calcium for the delivery of genetic products, especially for small interfering RNA (siRNA). This combination strategy remedies the reduced internalization efficiency caused by neutralization. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides)
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