Pharmaceutics

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19 pages, 3151 KiB

Open AccessEditor’s ChoiceArticle

Stem Cell Bioengineering with Bioportides: Inhibition of Planarian Head Regeneration with Peptide Mimetics of Eyes Absent Proteins

by Sarah Jones, Bárbara Matos, Sarah Dennison, Margarida Fardilha and John Howl

Pharmaceutics 2023, 15(8), 2018; https://doi.org/10.3390/pharmaceutics15082018 - 26 Jul 2023

Viewed by 934

Abstract

Djeya1 (RKLAFRYRRIKELYNSYR) is a very effective cell penetrating peptide (CPP) that mimics the α5 helix of the highly conserved Eya domain (ED) of eyes absent (Eya) proteins. The objective of this study was to bioengineer analogues of Djeya1 that, following effective translocation into [...] Read more.

Djeya1 (RKLAFRYRRIKELYNSYR) is a very effective cell penetrating peptide (CPP) that mimics the α5 helix of the highly conserved Eya domain (ED) of eyes absent (Eya) proteins. The objective of this study was to bioengineer analogues of Djeya1 that, following effective translocation into planarian tissues, would reduce the ability of neoblasts (totipotent stem cells) and their progeny to regenerate the anterior pole in decapitated S. mediterranea. As a strategy to increase the propensity for helix formation, molecular bioengineering of Djeya1 was achieved by the mono-substitution of the helicogenic aminoisobutyric acid (Aib) at three species-variable sites: 10, 13, and 16. CD analyses indicated that Djeya1 is highly helical, and that Aib-substitution had subtle influences upon the secondary structures of bioengineered analogues. Aib-substituted Djeya1 analogues are highly efficient CPPs, devoid of influence upon cell viability or proliferation. All three peptides increase the migration of PC-3 cells, a prostate cancer line that expresses high concentrations of Eya. Two peptides, [Aib¹³]Djeya1 and [Aib¹⁶]Djeya1, are bioportides which delay planarian head regeneration. As neoblasts are the only cell population capable of division in planaria, these data indicate that bioportide technologies could be utilised to directly manipulate other stem cells in situ, thus negating any requirement for genetic manipulation. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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15 pages, 2774 KiB

Open AccessArticle

Stereoisomer-Dependent Membrane Association and Capacity for Insulin Delivery Facilitated by Penetratin

by Ditlev Birch, Edward J. Sayers, Malene V. Christensen, Arwyn T. Jones, Henrik Franzyk and Hanne M. Nielsen

Pharmaceutics 2023, 15(6), 1672; https://doi.org/10.3390/pharmaceutics15061672 - 07 Jun 2023

Cited by 3 | Viewed by 1110

Abstract

Cell-penetrating peptides (CPPs), such as penetratin, are often investigated as drug delivery vectors and incorporating d-amino acids, rather than the natural l-forms, to enhance proteolytic stability could improve their delivery efficiency. The present study aimed to compare membrane association, cellular uptake, [...] Read more.

Cell-penetrating peptides (CPPs), such as penetratin, are often investigated as drug delivery vectors and incorporating d-amino acids, rather than the natural l-forms, to enhance proteolytic stability could improve their delivery efficiency. The present study aimed to compare membrane association, cellular uptake, and delivery capacity for all-l and all-d enantiomers of penetratin (PEN) by using different cell models and cargos. The enantiomers displayed widely different distribution patterns in the examined cell models, and in Caco-2 cells, quenchable membrane binding was evident for d-PEN in addition to vesicular intracellular localization for both enantiomers. The uptake of insulin in Caco-2 cells was equally mediated by the two enantiomers, and while l-PEN did not increase the transepithelial permeation of any of the investigated cargo peptides, d-PEN increased the transepithelial delivery of vancomycin five-fold and approximately four-fold for insulin at an extracellular apical pH of 6.5. Overall, while d-PEN was associated with the plasma membrane to a larger extent and was superior in mediating the transepithelial delivery of hydrophilic peptide cargoes compared to l-PEN across Caco-2 epithelium, no enhanced delivery of the hydrophobic cyclosporin was observed, and intracellular insulin uptake was induced to a similar degree by the two enantiomers. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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12 pages, 980 KiB

Open AccessFeature PaperArticle

The Balance between Hydrophobicity/Aromaticity and Positively Charged Residues May Influence the Cell Penetration Ability

by Dóra Soltész, Ildikó Szabó and Zoltán Bánóczi

Pharmaceutics 2023, 15(4), 1267; https://doi.org/10.3390/pharmaceutics15041267 - 18 Apr 2023

Cited by 2 | Viewed by 1042

Abstract

Cell-penetrating peptides (CPPs) are commonly modified to increase their cellular uptake, alter the mechanism of penetration or enhance their endosomal release. Earlier, we described the internalization enhancement ability of the 4-((4-(dimethylamino)phenyl)azo)benzoyl (Dabcyl) group. We proved that this modification on the N-terminus of tetra- [...] Read more.

Cell-penetrating peptides (CPPs) are commonly modified to increase their cellular uptake, alter the mechanism of penetration or enhance their endosomal release. Earlier, we described the internalization enhancement ability of the 4-((4-(dimethylamino)phenyl)azo)benzoyl (Dabcyl) group. We proved that this modification on the N-terminus of tetra- and hexaarginine enhanced their cellular uptake. The introduction of an aromatic ring 4-(aminomethyl) benzoic acid, AMBA) into the peptide backbone has a synergistic effect with Dabcyl, and the tetraarginine derivatives had outstanding cellular uptake. Based on these results, the effect of Dabcyl or Dabcyl-AMBA modification on the internalization of oligoarginines was studied. Oligoarginines were modified with these groups and their internalization was measured using flow cytometry. The concentration dependence of the cellular uptake of selected constructs was compared too. Their internalization mechanism was also examined by using different endocytosis inhibitors. While the effect of the Dabcyl group was optimal for hexaarginine, the Dabcyl-AMBA group increased the cellular uptake in the case of all oligoarginines. All derivatives, with the exception of only tetraarginine, were more effective than the octaarginine control. The internalization mechanism was dependent on the size of the oligoarginine and was independent of the modification. Our findings suggest that these modifications enhanced the internalization of oligoarginines and resulted in novel, very effective CPPs. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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15 pages, 3251 KiB

Open AccessArticle

Inhibition of Hepatitis B Virus (HBV) by Tachyplesin, a Marine Antimicrobial Cell-Penetrating Peptide

by Pankhuri Narula, Sankar Kiruthika, Shruti Chowdhari, Perumal Vivekanandan and Archana Chugh

Pharmaceutics 2023, 15(2), 672; https://doi.org/10.3390/pharmaceutics15020672 - 16 Feb 2023

Cited by 1 | Viewed by 1672

Abstract

We investigate the role of Tachyplesin (Tpl), a marine antimicrobial cell-penetrating peptide, as an anti-HBV agent. Our findings, using confocal microscopy and flow cytometry, demonstrate the internalization of FITC-Tpl in both Huh7 and HepG2 cell lines. Further, our results show that Tpl inhibits [...] Read more.

We investigate the role of Tachyplesin (Tpl), a marine antimicrobial cell-penetrating peptide, as an anti-HBV agent. Our findings, using confocal microscopy and flow cytometry, demonstrate the internalization of FITC-Tpl in both Huh7 and HepG2 cell lines. Further, our results show that Tpl inhibits the expression of HBV proteins, including hepatitis B surface antigen (HBsAg) and hepatitis B ‘e’ antigen (HBeAg) in cell supernatants of human liver cell lines transfected with 1.3× pHBV. Interestingly Tpl also reduces levels of HBV pre-core RNA and HBV pregenomic RNA, suggesting that Tpl-mediated inhibition occurs at the early stages of HBV replication, including viral transcription. In addition, Tpl led to a significant reduction in levels of hepatitis B virion secretion. In sum, here we demonstrate the potent anti-HBV activity of Tpl at non-cytotoxic concentrations indicating the potential of Tpl to emerge as an effective therapeutic peptide against HBV. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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20 pages, 3879 KiB

Open AccessArticle

Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery

by Abhijit Biswas, Maria Maloverjan, Kärt Padari, Aare Abroi, Margus Rätsep, Sebastian K. T. S. Wärmländer, Jüri Jarvet, Astrid Gräslund, Vambola Kisand, Rünno Lõhmus and Margus Pooga

Pharmaceutics 2023, 15(2), 396; https://doi.org/10.3390/pharmaceutics15020396 - 24 Jan 2023

Cited by 2 | Viewed by 1769

Abstract

Cell-penetrating peptides (CPPs) are highly promising transfection agents that can deliver various compounds into living cells, including nucleic acids (NAs). Positively charged CPPs can form non-covalent complexes with negatively charged NAs, enabling simple and time-efficient nanoparticle preparation. However, as CPPs have substantially different [...] Read more.

Cell-penetrating peptides (CPPs) are highly promising transfection agents that can deliver various compounds into living cells, including nucleic acids (NAs). Positively charged CPPs can form non-covalent complexes with negatively charged NAs, enabling simple and time-efficient nanoparticle preparation. However, as CPPs have substantially different chemical and physical properties, their complexation with the cargo and characteristics of the resulting nanoparticles largely depends on the properties of the surrounding environment, i.e., solution. Here, we show that the solvent used for the initial dissolving of a CPP determines the properties of the resulting CPP particles formed in an aqueous solution, including the activity and toxicity of the CPP–NA complexes. Using different biophysical methods such as dynamic light scattering (DLS), atomic force microscopy (AFM), transmission and scanning electron microscopy (TEM and SEM), we show that PepFect14 (PF14), a cationic amphipathic CPP, forms spherical particles of uniform size when dissolved in organic solvents, such as ethanol and DMSO. Water-dissolved PF14, however, tends to form micelles and non-uniform aggregates. When dissolved in organic solvents, PF14 retains its α-helical conformation and biological activity in cell culture conditions without any increase in cytotoxicity. Altogether, our results indicate that by using a solvent that matches the chemical nature of the CPP, the properties of the peptide–cargo particles can be tuned in the desired way. This can be of critical importance for in vivo applications, where CPP particles that are too large, non-uniform, or prone to aggregation may induce severe consequences. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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12 pages, 3055 KiB

Open AccessArticle

Fluid-Phase Endocytosis and Lysosomal Degradation of Bovine Lactoferrin in Lung Cells

by Edward John Sayers, Iwan Palmer, Lucy Hope, Paul Hope, Peter Watson and Arwyn Tomos Jones

Pharmaceutics 2022, 14(4), 855; https://doi.org/10.3390/pharmaceutics14040855 - 13 Apr 2022

Cited by 2 | Viewed by 2408

Abstract

The iron-binding protein lactoferrin and the cell-penetrating peptides derived from its sequence utilise endocytosis to enter different cell types. The full-length protein has been extensively investigated as a potential therapeutic against a range of pathogenic bacteria, fungi, and viruses, including SARS-CoV-2. As a [...] Read more.

The iron-binding protein lactoferrin and the cell-penetrating peptides derived from its sequence utilise endocytosis to enter different cell types. The full-length protein has been extensively investigated as a potential therapeutic against a range of pathogenic bacteria, fungi, and viruses, including SARS-CoV-2. As a respiratory antiviral agent, several activity mechanisms have been demonstrated for lactoferrin, at the extracellular and plasma membrane levels, but as a protein that enters cells it may also have intracellular antiviral activity. Characterisation of lactoferrin’s binding, endocytic traffic to lysosomes, or recycling endosomes for exocytosis is lacking, especially in lung cell models. Here, we use confocal microscopy, flow cytometry, and degradation assays to evaluate binding, internalisation, endocytic trafficking, and the intracellular fate of bovine lactoferrin in human lung A549 cells. In comparative studies with endocytic probes transferrin and dextran, we show that lactoferrin binds to negative charges on the cell surface and actively enters cells via fluid-phase endocytosis, in a receptor-independent manner. Once inside the cell, we show that it is trafficked to lysosomes where it undergoes degradation within two hours. These findings provide opportunities for investigating both lactoferrin and derived cell-penetrating peptides activities of targeting intracellular pathogens. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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17 pages, 3290 KiB

Open AccessArticle

Highway to Cell: Selection of the Best Cell-Penetrating Peptide to Internalize the CFTR-Stabilizing iCAL36 Peptide

by Quentin Seisel, Israpong Lakumpa, Emilie Josse, Eric Vivès, Jessica Varilh, Magali Taulan-Cadars and Prisca Boisguérin

Pharmaceutics 2022, 14(4), 808; https://doi.org/10.3390/pharmaceutics14040808 - 07 Apr 2022

Cited by 5 | Viewed by 1796

Abstract

Therapeutic peptides have regained interest as they can address unmet medical needs and can be an excellent complement to pharmaceutic small molecules and other macromolecular therapeutics. Over the past decades, correctors and potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride [...] Read more.

Therapeutic peptides have regained interest as they can address unmet medical needs and can be an excellent complement to pharmaceutic small molecules and other macromolecular therapeutics. Over the past decades, correctors and potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel causing cystic fibrosis (CF) when mutated, were developed to reduce the symptoms of the patients. In this context, we have previously designed a CFTR-stabilizing iCAL36 peptide able to further increase the CFTR amount in epithelial cells, thereby resulting in a higher CFTR activity. In the present study, optimization of the peptidyl inhibitor was performed by coupling five different cell-penetrating peptides (CPP), which are Tat, dTat, TatRI (retro-inverso), MPG, and Penetratin. Screening of the internalization properties of these CPP-iCAL36 peptides under different conditions (with or without serum or endocytosis inhibitors, etc.) was performed to select TatRI as the optimal CPP for iCAL36 delivery. More importantly, using this TatRI-iCAL36 peptide, we were able to reveal for the first time an additive increase in the CFTR amount in the presence of VX-445/VX-809 compared to VX-445/VX-809 treatment alone. This finding is a significant contribution to the development of CFTR-stabilizing peptides in addition to currently used treatments (small-molecule correctors or potentiators) for CF patients. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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23 pages, 6071 KiB

Open AccessArticle

Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy

by Rúben Faria, Milan Paul, Swati Biswas, Eric Vivès, Prisca Boisguérin, Ângela Sousa and Diana Costa

Pharmaceutics 2022, 14(4), 757; https://doi.org/10.3390/pharmaceutics14040757 - 31 Mar 2022

Cited by 5 | Viewed by 2244

Abstract

Together with the nucleus, the mitochondrion has its own genome. Mutations in mitochondrial DNA are responsible for a variety of disorders, including neurodegenerative diseases and cancer. Current therapeutic approaches are not effective. In this sense, mitochondrial gene therapy emerges as a valuable and [...] Read more.

Together with the nucleus, the mitochondrion has its own genome. Mutations in mitochondrial DNA are responsible for a variety of disorders, including neurodegenerative diseases and cancer. Current therapeutic approaches are not effective. In this sense, mitochondrial gene therapy emerges as a valuable and promising therapeutic tool. To accomplish this goal, the design/development of a mitochondrial-specific gene delivery system is imperative. In this work, we explored the ability of novel polymer- and peptide-based systems for mitochondrial targeting, gene delivery, and protein expression, performing a comparison between them to reveal the most adequate system for mitochondrial gene therapy. Therefore, we synthesized a novel mitochondria-targeting polymer (polyethylenimine–dequalinium) to load and complex a mitochondrial-gene-based plasmid. The polymeric complexes exhibited physicochemical properties and cytotoxic profiles dependent on the nitrogen-to-phosphate-group ratio (N/P). A fluorescence confocal microscopy study revealed the mitochondrial targeting specificity of polymeric complexes. Moreover, transfection mediated by polymer and peptide delivery systems led to gene expression in mitochondria. Additionally, the mitochondrial protein was produced. A comparative study between polymeric and peptide/plasmid DNA complexes showed the great capacity of peptides to complex pDNA at lower N/P ratios, forming smaller particles bearing a positive charge, with repercussions on their capacity for cellular transfection, mitochondria targeting and, ultimately, gene delivery and protein expression. This report is a significant contribution to the implementation of mitochondrial gene therapy, instigating further research on the development of peptide-based delivery systems towards clinical translation. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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11 pages, 4452 KiB

Open AccessArticle

α/β-Peptides as Nanomolar Triggers of Lipid Raft-Mediated Endocytosis through GM1 Ganglioside Recognition

by Anasztázia Hetényi, Enikő Szabó, Norbert Imre, Kaushik Nath Bhaumik, Attila Tököli, Tamás Füzesi, Réka Hollandi, Peter Horvath, Ágnes Czibula, Éva Monostori, Mária A. Deli and Tamás A. Martinek

Pharmaceutics 2022, 14(3), 580; https://doi.org/10.3390/pharmaceutics14030580 - 07 Mar 2022

Cited by 1 | Viewed by 2172

Abstract

Cell delivery of therapeutic macromolecules and nanoparticles is a critical drug development challenge. Translocation through lipid raft-mediated endocytic mechanisms is being sought, as it can avoid rapid lysosomal degradation. Here, we present a set of short α/β-peptide tags with high affinity to the [...] Read more.

Cell delivery of therapeutic macromolecules and nanoparticles is a critical drug development challenge. Translocation through lipid raft-mediated endocytic mechanisms is being sought, as it can avoid rapid lysosomal degradation. Here, we present a set of short α/β-peptide tags with high affinity to the lipid raft-associated ganglioside GM1. These sequences induce effective internalization of the attached immunoglobulin cargo. The structural requirements of the GM1-peptide interaction are presented, and the importance of the membrane components are shown. The results contribute to the development of a receptor-based cell delivery platform. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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14 pages, 3686 KiB

Open AccessArticle

Improving Membrane Activity and Cargo Delivery Efficacy of a Cell-Penetrating Peptide by Loading with Carboranes

by Tamara Lützenburg, Nele Burdina, Matthias S. Scholz and Ines Neundorf

Pharmaceutics 2021, 13(12), 2075; https://doi.org/10.3390/pharmaceutics13122075 - 03 Dec 2021

Cited by 2 | Viewed by 2251

Abstract

Cell-penetrating peptides (CPPs) have emerged as versatile tools to increase the intracellular accumulation of different kinds of cargoes. For an efficient cellular uptake and drug delivery, their organization into a distinct and stable secondary structure at the outer surface of the plasma membrane [...] Read more.

Cell-penetrating peptides (CPPs) have emerged as versatile tools to increase the intracellular accumulation of different kinds of cargoes. For an efficient cellular uptake and drug delivery, their organization into a distinct and stable secondary structure at the outer surface of the plasma membrane is a hallmark and supports optimal lipid–peptide interactions. Incorporation of hydrophobic moieties, such as carboranes (CBs), has the potential to increase the lipophilicity of peptides, and thus, to facilitate the formation of secondary structures. Herein, we present synthesis and biophysical as well as biological characterization of carborane-CPP conjugates having incorporated one or more CB clusters. Our results highlight the possibility to modulate the secondary structure of CPPs by the addition of CB’s leading to constructs with altered membrane activity and promising use in terms of nucleic acid delivery. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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15 pages, 3157 KiB

Open AccessArticle

Bi-Functional Peptides as a New Therapeutic Tool for Hepatocellular Carcinoma

by Eric Savier, Lorena Simon-Gracia, Frederic Charlotte, Pierre Tuffery, Tambet Teesalu, Olivier Scatton and Angelita Rebollo

Pharmaceutics 2021, 13(10), 1631; https://doi.org/10.3390/pharmaceutics13101631 - 06 Oct 2021

Cited by 7 | Viewed by 1851

Abstract

Background: The interfering peptides that block protein–protein interactions have been receiving increasing attention as potential therapeutic tools. Methods: We measured the internalization and biological effect of four bi-functional tumor-penetrating and interfering peptides into primary hepatocytes isolated from three non-malignant and 11 hepatocellular carcinomas. [...] Read more.

Background: The interfering peptides that block protein–protein interactions have been receiving increasing attention as potential therapeutic tools. Methods: We measured the internalization and biological effect of four bi-functional tumor-penetrating and interfering peptides into primary hepatocytes isolated from three non-malignant and 11 hepatocellular carcinomas. Results: These peptides are internalized in malignant hepatocytes but not in non-malignant cells. Furthermore, the degree of peptide internalization correlated with receptor expression level and tumor aggressiveness levels. Importantly, penetration of the peptides iRGD-IP, LinTT1-IP, TT1-IP, and RPARPAR-IP induced apoptosis of the malignant hepatocytes without effect on non-malignant cells. Conclusion: Receptor expression levels correlated with the level of peptide internalization and aggressiveness of the tumor. This study highlights the potential to exploit the expression of tumor-penetrating peptide receptors as a predictive marker of liver tumor aggressiveness. These bi-functional peptides could be developed for personalized tumor treatment. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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13 pages, 2488 KiB

Open AccessArticle

B3Pred: A Random-Forest-Based Method for Predicting and Designing Blood–Brain Barrier Penetrating Peptides

by Vinod Kumar, Sumeet Patiyal, Anjali Dhall, Neelam Sharma and Gajendra Pal Singh Raghava

Pharmaceutics 2021, 13(8), 1237; https://doi.org/10.3390/pharmaceutics13081237 - 11 Aug 2021

Cited by 22 | Viewed by 4529

Abstract

The blood–brain barrier is a major obstacle in treating brain-related disorders, as it does not allow the delivery of drugs into the brain. We developed a method for predicting blood–brain barrier penetrating peptides to facilitate drug delivery into the brain. These blood–brain barrier [...] Read more.

The blood–brain barrier is a major obstacle in treating brain-related disorders, as it does not allow the delivery of drugs into the brain. We developed a method for predicting blood–brain barrier penetrating peptides to facilitate drug delivery into the brain. These blood–brain barrier penetrating peptides (B3PPs) can act as therapeutics, as well as drug delivery agents. We trained, tested, and evaluated our models on blood–brain barrier peptides obtained from the B3Pdb database. First, we computed a wide range of peptide features. Then, we selected relevant peptide features. Finally, we developed numerous machine-learning-based models for predicting blood–brain barrier peptides using the selected features. The random-forest-based model performed the best with respect to the top 80 selected features and achieved a maximal 85.08% accuracy with an AUROC of 0.93. We also developed a webserver, B3pred, that implements our best models. It has three major modules that allow users to predict/design B3PPs and scan B3PPs in a protein sequence. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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Review

Jump to: Research

9 pages, 1016 KiB

Open AccessReview

Cell-Penetrating Peptides with Unexpected Anti-Amyloid Properties

by Nicklas Österlund, Sebastian K. T. S. Wärmländer and Astrid Gräslund

Pharmaceutics 2022, 14(4), 823; https://doi.org/10.3390/pharmaceutics14040823 - 09 Apr 2022

Cited by 7 | Viewed by 2214

Abstract

Cell-penetrating peptides (CPPs) with sequences derived originally from a prion protein (PrP) have been shown to exhibit both anti-prion and anti-amyloid properties particularly against prion proteins and the amyloid-β (Aβ) peptide active in Alzheimer’s disease. These disease-modifying properties are so far observed in [...] Read more.

Cell-penetrating peptides (CPPs) with sequences derived originally from a prion protein (PrP) have been shown to exhibit both anti-prion and anti-amyloid properties particularly against prion proteins and the amyloid-β (Aβ) peptide active in Alzheimer’s disease. These disease-modifying properties are so far observed in cell cultures and in vitro. The CPP sequences are composed of a hydrophobic signal sequence followed by a highly positively charged hexapeptide segment. The original signal sequence of the prion protein can be changed to the signal sequence of the NCAM1 protein without losing the anti-prion activity. Although the detailed molecular mechanisms of these CPP peptides are not fully understood, they do form amyloid aggregates by themselves, and molecular interactions between the CPPs and PrP/Aβ can be observed in vitro using various spectroscopic techniques. These initial intermolecular interactions appear to re-direct the aggregation pathways for prion/amyloid formation to less cell-toxic molecular structures (i.e., co-aggregates), which likely is why the disease-inducing PrP/Aβ aggregation is counteracted in vivo. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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31 pages, 2954 KiB

Open AccessReview

Cell-Penetrating Peptides and Transportan

by Ülo Langel

Pharmaceutics 2021, 13(7), 987; https://doi.org/10.3390/pharmaceutics13070987 - 29 Jun 2021

Cited by 22 | Viewed by 3850

Abstract

In the most recent 25–30 years, multiple novel mechanisms and applications of cell-penetrating peptides (CPP) have been demonstrated, leading to novel drug delivery systems. In this review, I present a brief introduction to the CPP area with selected recent achievements. This is followed [...] Read more.

In the most recent 25–30 years, multiple novel mechanisms and applications of cell-penetrating peptides (CPP) have been demonstrated, leading to novel drug delivery systems. In this review, I present a brief introduction to the CPP area with selected recent achievements. This is followed by a nostalgic journey into the research in my own laboratories, which lead to multiple CPPs, starting from transportan and paving a way to CPP-based therapeutic developments in the delivery of bio-functional materials, such as peptides, proteins, vaccines, oligonucleotides and small molecules, etc. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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