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Special Issue "Cell Penetrating Peptides (CPPs)"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 April 2015)

Special Issue Editor

Guest Editor
Prof. Dr. Marc Devocelle

RCSI Pharmaceutical & Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland
Website | E-Mail
Phone: +353 14022176
Interests: peptide chemistry; peptides and peptidomimetics as drug candidates and investigational tools; peptide-based drug delivery systems and nanomedicines; peptide-functionalised biomaterials

Special Issue Information

Dear Colleagues,

In less than 25 years, Cell Penetrating Peptides (CPPs) have progressed from challenging a paradigm to entering clinical trials, with at least two candidates reaching Phase III. Counterintuitively, though charged molecules and hydrophilic biopolymers are inherently prevented from crossing phospholipid bilayers, CPPs, peptide sequences 5- to 30-amino acid long generally displaying high net charges, possess the ability to efficiently translocate cell membranes and deliver a broad range of cargoes intracellularly.

The capacity of CPPs to reach intracellular targets significantly expand the pharmacological target space: 60% of current drug targets, addressed essentially by low molecular weight agents, are extracellular, but cell surface proteins represent only 22% of the proteins encoded by the human genome and a 2 to 30 fold increase in the number of drug targets could arise from the sequencing of the human genome. Also, biologics, macromolecular agents with limited membrane translocation abilities, are becoming one of the fastest growing classes of new therapeutics, accounting already for 20–25% of all new drug approvals.

CPPs can transport low molecular weight agents, proteins, nucleic acids, polymers, nanoparticles and liposomes through cell membranes and also through the blood–brain barrier. Furthermore, their interest is not limited to a wealth of potential therapeutic and/or imaging applications, they are also fundamental tools to study cell membrane dynamics and structure, including curvature, and cell entry mechanisms. CPPs have been instrumental in the implementation and development of biochemical, biophysical and functional assays and of molecular dynamic simulations, in experiments delineating the structural requirements for cell internalisation. Potentially permeating cells indiscriminately, CPPs can also achieve three levels of targeting selectivities, tissue, cell and organelle.

Prof. Dr. Marc Devocelle
Gest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.


Keywords

  • intracellular delivery
  • membrane dynamics
  • endocytosis, direct translocation
  • cationic, amphipathic, hydrophobic properties
  • molecular, biological, supramolecular cargoes

Related Special Issue

Published Papers (5 papers)

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Research

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Open AccessArticle Comparative Immunogenicity of a Cytotoxic T Cell Epitope Delivered by Penetratin and TAT Cell Penetrating Peptides
Molecules 2015, 20(8), 14033-14050; doi:10.3390/molecules200814033
Received: 1 May 2015 / Revised: 16 July 2015 / Accepted: 29 July 2015 / Published: 3 August 2015
Cited by 5 | PDF Full-text (1355 KB) | HTML Full-text | XML Full-text
Abstract
Cell penetrating peptides (CPP), including the TAT peptide from the human immunodeficiency virus transactivator of transcription (HIV-TAT) protein and penetratin from Drosophila Antennapedia homeodomain protein, translocate various cargos including peptides and proteins across cellular barriers. This mode of delivery has been harnessed by
[...] Read more.
Cell penetrating peptides (CPP), including the TAT peptide from the human immunodeficiency virus transactivator of transcription (HIV-TAT) protein and penetratin from Drosophila Antennapedia homeodomain protein, translocate various cargos including peptides and proteins across cellular barriers. This mode of delivery has been harnessed by our group and others to deliver antigenic proteins or peptides into the cytoplasm of antigen processing cells (APC) such as monocyte-derived dendritic cells (MoDC). Antigens or T cell epitopes delivered by CPP into APC in vivo generate antigen-specific cytotoxic T cell and helper T cell responses in mice. Furthermore, mice immunised with these peptides or proteins are protected from a tumour challenge. The functional properties of CPP are dependent on the various cargos being delivered and the target cell type. Despite several studies demonstrating superior immunogenicity of TAT and Antp-based immunogens, none has compared the immunogenicity of antigens delivered by TAT and Antp CPP. In the current study we demonstrate that a cytotoxic T cell epitope from the mucin 1 (MUC1) tumour associated antigen, when delivered by TAT or Antp, generates identical immune responses in mice resulting in specific MUC1 T cell responses as measured by in vivo CTL assays, IFNγ ELISpot assays and prophylactic tumour protection. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides (CPPs))
Open AccessArticle Development of Radiolabeled Membrane Type-1 Matrix Metalloproteinase Activatable Cell Penetrating Peptide Imaging Probes
Molecules 2015, 20(7), 12076-12092; doi:10.3390/molecules200712076
Received: 29 April 2015 / Revised: 7 June 2015 / Accepted: 29 June 2015 / Published: 2 July 2015
Cited by 2 | PDF Full-text (911 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Membrane type-1 matrix metalloproteinase (MT1-MMP or MMP-14) plays an important role in adverse cardiac remodelling. Here, we aimed to develop radiolabeled activatable cell penetrating peptides (ACPP) sensitive to MT1-MMP for the detection of elevated MT1-MMP levels in adverse cardiac remodelling. Three ACPP analogs
[...] Read more.
Membrane type-1 matrix metalloproteinase (MT1-MMP or MMP-14) plays an important role in adverse cardiac remodelling. Here, we aimed to develop radiolabeled activatable cell penetrating peptides (ACPP) sensitive to MT1-MMP for the detection of elevated MT1-MMP levels in adverse cardiac remodelling. Three ACPP analogs were synthesized and the most potent ACPP analog was selected using MT1-MMP sensitivity and enzyme specificity assays. This ACPP, called ACPP-B, showed high sensitivity towards MT1-MMP, soluble MMP-2, and MT2-MMP, while limited sensitivity was measured for other members of the MMP family. In in vitro cell assays, radiolabeled ACPP-B showed efficient cellular uptake upon activation. A pilot in vivo study showed increased uptake of the radiolabeled probe in regions of infarcted myocardium compared to remote myocardium, warranting further in vivo evaluation. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides (CPPs))
Figures

Open AccessArticle NKCS, a Mutant of the NK-2 Peptide, Causes Severe Distortions and Perforations in Bacterial, But Not Human Model Lipid Membranes
Molecules 2015, 20(4), 6941-6958; doi:10.3390/molecules20046941
Received: 30 January 2015 / Revised: 9 April 2015 / Accepted: 10 April 2015 / Published: 16 April 2015
Cited by 1 | PDF Full-text (3095 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
NKCS is an improved mutant of the bioactive peptide NK-2, which shows strong activity against Escherichia coli and low toxicity towards human cells. The different activity demonstrates the relevance of the physico-chemical nature of the target membrane for the biological effect of this
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NKCS is an improved mutant of the bioactive peptide NK-2, which shows strong activity against Escherichia coli and low toxicity towards human cells. The different activity demonstrates the relevance of the physico-chemical nature of the target membrane for the biological effect of this peptide. We studied the effect of this potent antimicrobial peptide on model membranes by activity studies, differential scanning calorimetry, single molecule tracking and tracer efflux experiments. We found that NKCS severely distorted, penetrated and perforated model lipid membranes that resembled bacterial membranes, but not those that were similar to human cell membranes. The interactions of NKCS with phosphatidylethanolamine, which is abundant in bacterial membranes, were especially strong and are probably responsible for its antimicrobial activity. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides (CPPs))
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Review

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Open AccessReview Cell-Penetrating Peptides: Possibilities and Challenges for Drug Delivery in Vitro and in Vivo
Molecules 2015, 20(7), 13313-13323; doi:10.3390/molecules200713313
Received: 28 April 2015 / Revised: 10 June 2015 / Accepted: 9 July 2015 / Published: 22 July 2015
Cited by 15 | PDF Full-text (1290 KB) | HTML Full-text | XML Full-text
Abstract
In this review, we discuss how cell-penetrating peptides (CPPs) might get access to their intracellular targets. We specifically focus on the challenge of deciding whether the positively-charged CPPs are just bound to the negatively-charged cell surface and subsequently endocytosed or actually transported into
[...] Read more.
In this review, we discuss how cell-penetrating peptides (CPPs) might get access to their intracellular targets. We specifically focus on the challenge of deciding whether the positively-charged CPPs are just bound to the negatively-charged cell surface and subsequently endocytosed or actually transported into the cytosol, either by direct plasma membrane penetration or after endocytosis. This discussion includes comments about pitfalls when using pharmacological inhibitors in such studies. The possibility of exploiting CPPs as carriers for the delivery of drugs of different sizes in vitro is discussed, as is the use of CPPs as carriers for therapeutic drugs or contrast agents in vivo. We conclude that in many cases, more studies are needed to demonstrate conclusively whether increased delivery of a substance attached to CPPs is due to a membrane-penetrating property or whether the increase is a consequence of just changing the charge of the substance to be delivered. Finally, the expected dose needed for the use of such conjugates in vivo is discussed, including aspects to consider in order to bring potential products into clinical use. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides (CPPs))
Figures

Open AccessReview Cell-Type Specific Penetrating Peptides: Therapeutic Promises and Challenges
Molecules 2015, 20(7), 13055-13070; doi:10.3390/molecules200713055
Received: 3 June 2015 / Revised: 19 June 2015 / Accepted: 10 July 2015 / Published: 20 July 2015
Cited by 15 | PDF Full-text (722 KB) | HTML Full-text | XML Full-text
Abstract
Cell penetrating peptides (CPP), also known as protein transduction domains (PTD), are small peptides able to carry peptides, proteins, nucleic acid, and nanoparticles, including viral particles, across the cellular membranes into cells, resulting in internalization of the intact cargo. In general, CPPs can
[...] Read more.
Cell penetrating peptides (CPP), also known as protein transduction domains (PTD), are small peptides able to carry peptides, proteins, nucleic acid, and nanoparticles, including viral particles, across the cellular membranes into cells, resulting in internalization of the intact cargo. In general, CPPs can be broadly classified into tissue-specific and non-tissue specific peptides, with the latter further sub-divided into three types: (1) cationic peptides of 6–12 amino acids in length comprised predominantly of arginine, lysine and/or ornithine residues; (2) hydrophobic peptides such as leader sequences of secreted growth factors or cytokines; and (3) amphipathic peptides obtained by linking hydrophobic peptides to nuclear localizing signals. Tissue-specific peptides are usually identified by screening of large peptide phage display libraries. These transduction peptides have the potential for a myriad of diagnostic as well as therapeutic applications, ranging from delivery of fluorescent or radioactive compounds for imaging, to delivery of peptides and proteins of therapeutic potential, and improving uptake of DNA, RNA, siRNA and even viral particles. Here we review the potential applications as well as hurdles to the tremendous potential of these CPPs, in particular the cell-type specific peptides. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides (CPPs))
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