Special Issue "Cell-penetrating Peptides"

Guest Editor
Prof. Dr. Vladimir P. Torchilin
Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Mugar Building, Room 312, 360 Huntington Avenue, Boston, MA 02115, USA
Website: http://www.pharmsci.neu.edu/faculty/torchilin.html
E-Mail:

Dear Colleagues,

Intracellular delivery of therapeutic molecules is one of the key problems in drug delivery in general. Many pharmaceutical agents should be delivered intracellularly to exert their therapeutic action inside cytoplasm or onto individual organelles, such as nuclei, lysosomes, or mitochondria. However, cell membranes prevent proteins, peptides, and nanoparticulate drug carriers from entering cells. So far, multiple and only partially successful attempts have been made to bring various drugs and drug-loaded pharmaceutical carriers directly into the cell cytoplasm bypassing the endocytic pathway, to protect drugs and DNA from the lysosomal degradation.

A promising approach that seems to be the solution of overcoming the cellular barrier for intracellular drug delivery has emerged over the last decade. In this approach, certain proteins or peptides can be tethered to the hydrophilic drug of interest and together the construct possesses the ability to translocate across the plasma membrane and deliver the payload intracellularly; the process termed as “protein transduction”. Such proteins or peptides contain domains of less than 20 amino acids, Protein Transduction Domains (PTDs) or Cell Penetrating Peptides (CPPs) that are highly rich in basic residues. These peptides have been used for intracellular delivery of various cargoes with molecular weights significantly greater than their own. This special issue will be dealing with pharmaceutical application of cell-penetrating peptides – a challenging and promising area in pharmaceutical research.

Prof. Dr. Vladimir P. Torchilin
Guest Editor

Submission Information

All papers should be submitted to pharmaceuticals@mdpi.org. To be published continuously until the deadline and papers will be listed together at the special issue website.

Submitted papers should not have been published nor be under consideration for publication elsewhere. All papers are refereed through a peer-review process. A guide for authors is available on the Instructions for Authors page. Pharmaceuticals is a new international, peer-reviewed, quarterly open access journal published by Molecular Diversity Preservation International.

Article Processing Charges (APC) for publication in this open access journal are waived for well-prepared manuscripts submitted by 30 June 2010. English correction or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those paper accepted for publication, that require extensive additional formatting and/or English corrections.

• intracellular delivery
• cell-penetrating peptides
• protein transduction domains
• drug targeting
• pharmaceutical nanocarriers

Manuscript ID: Pharmaceuticals-cpp-20090702-Ruzza-it
Title: A comparative studies on lipid affinity of cell penetrating peptides in presence or absence of cargo
Type of paper: Article
Author: Paolo Ruzza, E-mail: paolo.ruzza@unipd.it
Abstract: A growing number of natural and /or synthetic peptides with cell membrane penetrating capability have been identified and described in the past years. These molecules have been considered as targeting structures for the delivery of bioactive compounds into various cell types. Although the mechanism of uptake is still unclear, it is reasonable to assume that the relative contribute of each proposed mechanism could differ for the same peptide, depending on experimental protocol and cargo molecule composition. In this work we try to connect the capability to interact with model lipid membrane of CPP and their structural and chemical characteristics in order to obtain a biophysical classification that predicts the behavior of CPP-cargo molecule in cell system. Indeed, the interaction with cell membrane is one of the primary step in the interaction of CPP with cells, and consequently the studies on model membrane could become important for understanding peptide-membrane interaction on a molecular level, explaining how CPPs may translocate a membrane without destroying it and how this interactions come into play in shuttling CPPs via different routes with different efficiency. We analyzed by fluorescence spectroscopy the binding properties of six different CPPs (KFGF, Antp and Tat derived peptides, and oligoarginine peptides containing 6, 8 or 10 residues) in absence or presence of the same cargo peptide (the [392-401]pTyr³⁹⁶ fragment of HS1 protein). The binding properties were correlated to the conformational and chemical characteristic of peptides, as well as to the cell penetrating properties of the CPP-cargo conjugate. Results show that even if certain physico-chemical properties (conformation, positive charge, …) govern CPP capability to interact with the model membrane, these cannot fully explain cell-permeability properties.

Manuscript ID: pharmaceuticals-cpp-20090702-Giralt-es
Title: How to built cell selectivity into CPP-mediated strategies?
Type of paper: Review
Author: Ernest Giralt
Affiliation: Organic Chemistry Department , University of Barcelona, Spain
Abstract: An urgent need of more effective and selective therapies for cancer and other diseases is becoming a generalized claim. This is pushing forward alternative experimental approaches based on selective systems, which are designed to be specifically directed against target cells. In addition, a wide number of highly potent therapeutic molecules are currently being discovered. However they do not arrive to clinical trials due to their low delivery, poor specificity or their incapability to bypass the plasma membrane. CPPs are an open door for cell-impermeable compounds to reach intracellular targets. Putting all these together, research is sailing in the direction of the design of systems able to transport new drugs inside the target cell. CPPs are in some cases specific by themselves towards a cell type. In other cases, modifications are required, or they are part of more sophisticated drug delivery systems. In this review article we plan to summarize different strategies for directed drug delivery reported in the literature in which CPPs are implicated.

Manuscript ID: Pharmaceuticals-cpp-20090708- de Lima-pt
Type of Paper: Reivew
Title: Cell Penetrating Peptides – Mechanisms of Cellular Uptake and Generation of Nucleic Acid Delivery Systems
Authors: Sara Trabulo, Ana Luísa Cardoso, Miguel Mano, Maria Pedroso de Lima
Affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Portugal Department of Biochemistry, Faculty of Science and Technology, University of Coimbra, Portugal
Abstract: The successful clinical application of nucleic acid-based therapeutic strategies has been limited by the poor delivery efficiency achieved by existing vectors. Therefore, the development of alternative delivery systems for improved biological activity is mandatory. Cell penetrating peptides (CPPs) constitute one of the most promising tools that can be used to improve non-invasive cellular delivery of therapeutic molecules. Despite extensive research on the use of CPPs for this purpose, the exact mechanisms underlying their cellular uptake and that of peptide conjugates remain poorly understood.
Over the last years, our research group has been involved in the study of the S4₁₃-PV cell penetrating peptide, a chimeric peptide resulting from the combination of 13-amino-acid cell penetrating sequence derived from the Dermaseptin S4 peptide with the SV40 large T antigen nuclear localization signal. By performing an exhaustive biophysical and biochemical characterization of this peptide and its analogs, we have gained important insights into the mechanisms governing the interaction of CPPs with cells and their translocation across biological membranes. More recently, we have been exploring this peptide for the intracellular delivery of nucleic acids (plasmid DNA and siRNA).
In this review we will discuss the current knowledge on the mechanisms responsible for the cellular uptake of cell penetrating peptides, including the S4₁₃-PV peptide, and the potential of peptide-based formulations to mediate nucleic acid delivery.

Manuscript ID: Pharmceuticals-cpp-20090724-Divita-fr
Type of Paper: Review
Title: Cell Penetrating Peptide Based Nanoparticles: From Structure to Therapeutics
Authors: S. Deshayes, M.C. Morris, K. Konate and G, Divita
Affiliation: Centre de Recherches de Biochimie Macromoléculaire, CRBM-CNRS, UMR-5237, UM1-UM2, University of Montpellier, Department of Molecular Biophysics and Therapeutics, 1919 Route de Mende, 34293 Montpellier, France; Email: gilles.divita@crbm.cnrs.fr
Abstract: One of the major challenges for new therapeutic molecules to enter the clinic remains to improve their bioavailability and cellular uptake. Cell Penetrating Peptides (CPP) were identified twenty years ago, based on their potency to enter cells and nowadays, numerous peptide carriers have been described and successfully applied for ex-vivo and in vivo delivery of various therapeutic molecules. Two CPP-strategies have been reported, the first one requires chemical linkage between the drug and the carrier for cellular drug internalization and the second is based on the formation of stable complexes with drugs depending on their chemical nature. Cell Penetrating Peptide-Based nanoparticles significantly improve delivery of proteins and/or nucleic acids in a large variety of challenging cell lines as well as in animal models. This review will focus on the structure/function relationship of CPP-based nanoparticle and their applications for in vitro and in vivo delivery of therapeutic molecules.

Manuscript ID: pharmaceuticals-cpp-20090803-Dietz-de
Type of Article: article
Title: Application of cell-penetrating fragments of the CDK5 regulatory subunit in models for neurodegeneration
Authors: Jan Liman, Jochen H. Weishaupt, Mathias Bähr and Gunnar P. H. Dietz; E-mails: gdie@lundbeck.com and jliman@gwdg.de
Abstract: CDK5 is involved in many differentiation processes. CDK5 does not require the association with a cyclin, but the neuron-specific proteinP35 for activation. Cellular stress can lead to activation of calpain, which cleaves p35 into p25 resulting in an aberrant activation of CDK5. This mechanism is thought to be involved in neurodegenerative diseases. Different approaches have been made to inhibit pathological CDK5 activation, which were not always successful. ’Besides inhibiting pathological CDK5 activation as much downstream as possible, our approach also addresses one of the main challenges of drug delivery to the brain, which is to overcome the blood brain barrier. We have used a Tat linked dominant negative p25 fragment, which is binding, but not able to activate CDK5, thereby blocking the pathological CDK5 effects.