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Biomolecules
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Cell Penetrating Peptides
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Cell Penetrating Peptides

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (15 June 2018) | Viewed by 46427

Special Issue Editor

Prof. Dr. Jean-Philippe Pellois

E-Mail Website
Guest Editor
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA
Interests: protein engineering; membrane biochemistry; peptide/membrane interactions; cellular trafficking

Special Issue Information

Dear Colleagues, 

By having the ability to cross membranes, cell-penetrating peptides (CPPs) can enter cells and modulate cell physiology. CPPs can also serve as carriers that can deliver various macromolecules into cells. Consequently, CPPs are used in a wide array of applications with basic science, biotechnological, and therapeutic purposes. For instance, CPPs have been used to disrupt protein–protein interactions and modulate signal transduction pathways, to deliver nucleic acids to affect gene expression, to deliver fluorescent particles for microscopy-based investigations, to deliver transcription factors for cellular reprogramming, or to deliver radioisotopically-labeled proteins for in cellulo structure determination by NMR.   

By changing our views on what can and cannot enter a cell, CPPs have expanded the scope of what can be potentially done to manipulate or probe cells. They are also contributing to changing the notion of what may constitute a drug or a drug target. Concomitantly, they have also raised many questions. How do they enter cells? What do they do to cells, from the outside, at cellular membranes, and once inside the cell? What are the chemical and structural features that are required to achieve cell permeability? How can the efficiencies of cell targeting, endocytic uptake, or cytosolic penetration be increased? How can their properties be tuned to minimize cellular damage that may result from their membrane-disruption activities? Answering these questions remains an area of intense and exciting research, both in academia and in industry.

We invite scientist focusing on understanding, optimizing, and using CPPs to submit their original work or reviews. Both translational and basic research papers are welcome.

Prof. Dr. Jean-Philippe Pellois
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Biomolecules 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 2700 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

  • cell penetrating peptide
  • membrane translocation
  • drug delivery
  • cellular trafficking
  • protein transduction domains

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Published Papers (6 papers)

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Research

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16 pages, 2859 KiB  
Article
Cardiac Targeting Peptide, a Novel Cardiac Vector: Studies in Bio-Distribution, Imaging Application, and Mechanism of Transduction
by Maliha Zahid, Kyle S. Feldman, Gabriel Garcia-Borrero, Timothy N. Feinstein, Nicholas Pogodzinski, Xinxiu Xu, Raymond Yurko, Michael Czachowski, Yijen L. Wu, Neale S. Mason and Cecilia W. Lo
Biomolecules 2018, 8(4), 147; https://doi.org/10.3390/biom8040147 - 14 Nov 2018
Cited by 37 | Viewed by 8150
Abstract
Our previous work identified a 12-amino acid peptide that targets the heart, termed cardiac targeting peptide (CTP). We now quantitatively assess the bio-distribution of CTP, show a clinical application with the imaging of the murine heart, and study its mechanisms of transduction. Bio-distribution [...] Read more.
Our previous work identified a 12-amino acid peptide that targets the heart, termed cardiac targeting peptide (CTP). We now quantitatively assess the bio-distribution of CTP, show a clinical application with the imaging of the murine heart, and study its mechanisms of transduction. Bio-distribution studies of cyanine5.5-N-Hydroxysuccinimide (Cy5.5) labeled CTP were undertaken in wild-type mice. Cardiac targeting peptide was labeled with Technetium 99m (99mTc) using the chelator hydrazino-nicotinamide (HYNIC), and imaging performed using micro-single photon emission computerized tomography/computerized tomography (SPECT/CT). Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMCs) were incubated with dual-labeled CTP, and imaged using confocal microscopy. TriCEPs technology was utilized to study the mechanism of transduction. Bio-distribution studies showed peak uptake of CTP at 15 min. 99mTc-HYNIC-CTP showed heart-specific uptake. Robust transduction of beating human iPSC-derived CMCs was seen. TriCEPs experiments revealed five candidate binding partners for CTP, with Kcnh5 being felt to be the most likely candidate as it showed a trend towards being competed out by siRNA knockdown. Transduction efficiency was enhanced by increasing extracellular potassium concentration, and with Quinidine, a Kcnh5 inhibitor, that blocks the channel in an open position. We demonstrate that CTP transduces the normal heart as early as 15 min. 99mTc-HYNIC-CTP targets the normal murine heart with substantially improved targeting compared with 99mTc Sestamibi. Cardiac targeting peptide’s transduction ability is not species limited and has human applicability. Cardiac targeting peptide appears to utilize Kcnh5 to gain cell entry, a phenomenon that is affected by pre-treatment with Quinidine and changes in potassium levels. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides)
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13 pages, 693 KiB  
Article
Developments in Cell-Penetrating Peptides as Antiviral Agents and as Vehicles for Delivery of Peptide Nucleic Acid Targeting Hepadnaviral Replication Pathway
by Bénédicte Ndeboko, Olivier Hantz, Guy Joseph Lemamy and Lucyna Cova
Biomolecules 2018, 8(3), 55; https://doi.org/10.3390/biom8030055 - 16 Jul 2018
Cited by 13 | Viewed by 4843
Abstract
Alternative therapeutic approaches against chronic hepatitis B virus (HBV) infection need to be urgently developed because current therapies are only virostatic. In this context, cell penetration peptides (CPPs) and their Peptide Nucleic Acids (PNAs) cargoes appear as a promising novel class of biologically [...] Read more.
Alternative therapeutic approaches against chronic hepatitis B virus (HBV) infection need to be urgently developed because current therapies are only virostatic. In this context, cell penetration peptides (CPPs) and their Peptide Nucleic Acids (PNAs) cargoes appear as a promising novel class of biologically active compounds. In this review we summarize different in vitro and in vivo studies, exploring the potential of CPPs as vehicles for intracellular delivery of PNAs targeting hepadnaviral replication. Thus, studies conducted in the duck HBV (DHBV) infection model showed that conjugation of (D-Arg)8 CPP to PNA targeting viral epsilon (ε) were able to efficiently inhibit viral replication in vivo following intravenous administration to ducklings. Unexpectedly, some CPPs, (D-Arg)8 and Decanoyl-(D-Arg)8, alone displayed potent antiviral effect, altering late stages of DHBV and HBV morphogenesis. Such antiviral effects of CPPs may affect the sequence-specificity of CPP-PNA conjugates. By contrast, PNA conjugated to (D-Lys)4 inhibited hepadnaviral replication without compromising sequence specificity. Interestingly, Lactose-modified CPP mediated the delivery of anti-HBV PNA to human hepatoma cells HepaRG, thus improving its antiviral activity. In light of these promising data, we believe that future studies will open new perspectives for translation of CPPs and CPP-PNA based technology to therapy of chronic hepatitis B. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides)
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12 pages, 3058 KiB  
Article
β-Lactamase Tools for Establishing Cell Internalization and Cytosolic Delivery of Cell Penetrating Peptides
by Shane R. Stone, Tatjana Heinrich, Suzy M. Juraja, Jiulia N. Satiaputra, Clinton M. Hall, Mark Anastasas, Anna D. Mills, Christopher A. Chamberlain, Scott Winslow, Kristin Priebatsch, Paula T. Cunningham, Katrin Hoffmann and Nadia Milech
Biomolecules 2018, 8(3), 51; https://doi.org/10.3390/biom8030051 - 11 Jul 2018
Cited by 10 | Viewed by 5952
Abstract
The ability of cell penetrating peptides (CPPs) to deliver biologically relevant cargos into cells is becoming more important as targets in the intracellular space continue to be explored. We have developed two assays based on CPP-dependent, intracellular delivery of TEM-1 β-lactamase enzyme, a [...] Read more.
The ability of cell penetrating peptides (CPPs) to deliver biologically relevant cargos into cells is becoming more important as targets in the intracellular space continue to be explored. We have developed two assays based on CPP-dependent, intracellular delivery of TEM-1 β-lactamase enzyme, a functional biological molecule comparable in size to many protein therapeutics. The first assay focuses on the delivery of full-length β-lactamase to evaluate the internalization potential of a CPP sequence. The second assay uses a split-protein system where one component of β-lactamase is constitutively expressed in the cytoplasm of a stable cell line and the other component is delivered by a CPP. The delivery of a split β-lactamase component evaluates the cytosolic delivery capacity of a CPP. We demonstrate that these assays are rapid, flexible and have potential for use with any cell type and CPP sequence. Both assays are validated using canonical and novel CPPs, with limits of detection from <500 nM to 1 µM. Together, the β-lactamase assays provide compatible tools for functional characterization of CPP activity and the delivery of biological cargos into cells. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides)
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21 pages, 5186 KiB  
Article
A Novel Cell Penetrating Peptide for the Differentiation of Human Neural Stem Cells
by Weili Ma, Geun-woo Jin, Paul M. Gehret, Neil C. Chada and Won Hyuk Suh
Biomolecules 2018, 8(3), 48; https://doi.org/10.3390/biom8030048 - 9 Jul 2018
Cited by 8 | Viewed by 7756
Abstract
Retinoic acid (RA) is a bioactive lipid that has been shown to promote neural stem cell differentiation. However, the highly hydrophobic molecule needs to first solubilize and translocate across the cell membrane in order to exert a biological response. The cell entry of [...] Read more.
Retinoic acid (RA) is a bioactive lipid that has been shown to promote neural stem cell differentiation. However, the highly hydrophobic molecule needs to first solubilize and translocate across the cell membrane in order to exert a biological response. The cell entry of RA can be aided by cell penetrating peptides (CPPs), which are short amino acid sequences that are able to carry bioactive cargo past the cell membrane. In this work, a novel cell penetrating peptide was developed to deliver RA to human neural stem cells and, subsequently, promote neuronal differentiation. The novel CPP consists of a repeating sequence, whose number of repeats is proportional to the efficiency of cell penetration. Using fluorescence microscopy, the mode of translocation was determined to be related to an endocytic pathway. The levels of β-III tubulin (Tubb3) and microtubule associated protein 2 (MAP2) expression in neural stem cells treated with RA conjugated to the CPP were assessed by quantitative immunocytochemistry. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides)
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Review

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43 pages, 4263 KiB  
Review
Membrane Active Peptides and Their Biophysical Characterization
by Fatma Gizem Avci, Berna Sariyar Akbulut and Elif Ozkirimli
Biomolecules 2018, 8(3), 77; https://doi.org/10.3390/biom8030077 - 22 Aug 2018
Cited by 143 | Viewed by 12367
Abstract
In the last 20 years, an increasing number of studies have been reported on membrane active peptides. These peptides exert their biological activity by interacting with the cell membrane, either to disrupt it and lead to cell lysis or to translocate through it [...] Read more.
In the last 20 years, an increasing number of studies have been reported on membrane active peptides. These peptides exert their biological activity by interacting with the cell membrane, either to disrupt it and lead to cell lysis or to translocate through it to deliver cargos into the cell and reach their target. Membrane active peptides are attractive alternatives to currently used pharmaceuticals and the number of antimicrobial peptides (AMPs) and peptides designed for drug and gene delivery in the drug pipeline is increasing. Here, we focus on two most prominent classes of membrane active peptides; AMPs and cell-penetrating peptides (CPPs). Antimicrobial peptides are a group of membrane active peptides that disrupt the membrane integrity or inhibit the cellular functions of bacteria, virus, and fungi. Cell penetrating peptides are another group of membrane active peptides that mainly function as cargo-carriers even though they may also show antimicrobial activity. Biophysical techniques shed light on peptide–membrane interactions at higher resolution due to the advances in optics, image processing, and computational resources. Structural investigation of membrane active peptides in the presence of the membrane provides important clues on the effect of the membrane environment on peptide conformations. Live imaging techniques allow examination of peptide action at a single cell or single molecule level. In addition to these experimental biophysical techniques, molecular dynamics simulations provide clues on the peptide–lipid interactions and dynamics of the cell entry process at atomic detail. In this review, we summarize the recent advances in experimental and computational investigation of membrane active peptides with particular emphasis on two amphipathic membrane active peptides, the AMP melittin and the CPP pVEC. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides)
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13 pages, 2361 KiB  
Review
Efficient Delivery of Macromolecules into Human Cells by Improving the Endosomal Escape Activity of Cell-Penetrating Peptides: Lessons Learned from dfTAT and its Analogs
by Jason K. Allen, Dakota J. Brock, Helena M. Kondow-McConaghy and Jean-Philippe Pellois
Biomolecules 2018, 8(3), 50; https://doi.org/10.3390/biom8030050 - 11 Jul 2018
Cited by 39 | Viewed by 6214
Abstract
Cell-penetrating peptides (CPPs) are typically prone to endocytic uptake into human cells. However, they are often inefficient at escaping from endosomes, which limits their ability to deliver cargos into cells. This review highlights the efforts that our laboratory has devoted toward developing CPPs [...] Read more.
Cell-penetrating peptides (CPPs) are typically prone to endocytic uptake into human cells. However, they are often inefficient at escaping from endosomes, which limits their ability to deliver cargos into cells. This review highlights the efforts that our laboratory has devoted toward developing CPPs that can mediate the leakage of endosomal membranes, and consequently gain better access to the intracellular milieu. In particular, we have identified a CPP named dimeric fluorescent TAT (dfTAT) with high endosomolytic activity. We describe how we have used this reagent and its analogs to develop efficient cytosolic delivery protocols and learn about molecular and cellular parameters that control the cell permeation process. Specifically, we discuss how late endosomes represent exploitable gateways for intracellular entry. We also describe how certain features in CPPs, including guanidinium content, charge density, multimerization, chirality, and susceptibility to degradation modulate the activity that these peptidic agents take toward endosomal membranes and cytosolic egress. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides)
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