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Special Issue "Peptide-Based Drugs and Drug Delivery Systems"

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

Deadline for manuscript submissions: closed (30 May 2017)

Special Issue Editors

Guest Editor
Prof. Dr. Paula A. C. Gomes

UCIBIO-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal
Website1 | Website2 | E-Mail
Interests: medicinal chemistry; organic and peptide synthesis; anti-infective agents; anti-parasitic drugs; peptide-based drugs; drug delivery systems; biomaterials; biomedical engineering
Guest Editor
Prof. Dr. Stefania Galdiero

Department of Pharmacy, CIRPEB-University of Naples “Federico II”, Via Mezzocannone 16, 80134 Napoli, Italy
Website | E-Mail
Interests: peptides; liposomes; dendrimers; nanoparticles; drug delivery; antibacterial peptides; antiviral peptides

Special Issue Information

Dear Colleagues,

Peptides are ubiquitously found as relevant molecular tools in Research and Development, from Molecular Biology to Materials Science, from Synthetic Chemistry to Computational and Structural Biology, from Food Science to Biotechnology, from Early Drug Discovery to the Clinics, from Academia to Industry, etc, in summary, peptides offer no less than a whole world of possibilities to Science and Technology.

Over 150 peptide therapeutics have recently entered clinical trials, a number that remains low, as compared to that of small molecular drug candidates. Still, a paradigm shift in the Pharmaceutical Industry, regarding peptide-based drugs, is under way: until recent years, pharma companies have mostly put their bets on small molecules as drugs, leaving larger peptide-based candidates put aside, on the grounds of their low oral bioavailability and short half-life in vivo, among other limitations; however, small drugs often suffer from reduced selectivity, leading to unwanted off-target side effects, whereas peptides usually display an extraordinary specificity for their targets, which may largely compensate for their low bioavailability, poor permeability and susceptibility to metabolic inactivation. Moreover, chemical methods for peptide synthesis have been gaining efficacy, robustness and capability to produce peptides and peptidomimetics of increasing size and structural complexity, at overall production costs that have been steadily decreasing. Last, but not least, the emergent field of peptide-based materials for biomedical applications, has been gaining prominence.

In connection with the above, the present Special Issue is aimed at covering new approaches, methodologies, and perspectives towards development of peptide-based drugs, materials and drug delivery systems, for biomedical applications.

Prof. Dr. Paula A. C. Gomes
Prof. Dr. Stefania Galdiero
Guest Editors

Manuscript Submission Information

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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

  • antimicrobial Peptides
  • antiparasitic peptides
  • cell penetrating peptides
  • peptides and diabetes
  • collagen-stimulating peptides
  • peptide-based materials
  • peptide therapeutics
  • peptides in biomedical engineering
  • peptide synthesis
  • peptidomimetics

Published Papers (23 papers)

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Research

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Open AccessCommunication Biophysical Properties and Antiviral Activities of Measles Fusion Protein Derived Peptide Conjugated with 25-Hydroxycholesterol
Molecules 2017, 22(11), 1869; doi:10.3390/molecules22111869
Received: 13 July 2017 / Accepted: 26 October 2017 / Published: 31 October 2017
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Abstract
Measles virus (MV) infection is re-emerging, despite the availability of an effective vaccine. The mechanism of MV entry into a target cell relies on coordinated action between the MV hemagglutinin (H) receptor binding protein and the fusion envelope glycoprotein (F) which mediates fusion
[...] Read more.
Measles virus (MV) infection is re-emerging, despite the availability of an effective vaccine. The mechanism of MV entry into a target cell relies on coordinated action between the MV hemagglutinin (H) receptor binding protein and the fusion envelope glycoprotein (F) which mediates fusion between the viral and cell membranes. Peptides derived from the C-terminal heptad repeat (HRC) of F can interfere with this process, blocking MV infection. As previously described, biophysical properties of HRC-derived peptides modulate their antiviral potency. In this work, we characterized a MV peptide fusion inhibitor conjugated to 25-hydroxycholesterol (25HC), a cholesterol derivative with intrinsic antiviral activity, and evaluated its interaction with membrane model systems and human blood cells. The peptide (MV Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessFeature PaperCommunication A New Noncanonical Anionic Peptide That Translocates a Cellular Blood–Brain Barrier Model
Molecules 2017, 22(10), 1753; doi:10.3390/molecules22101753
Received: 28 September 2017 / Accepted: 14 October 2017 / Published: 18 October 2017
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Abstract
The capacity to transport therapeutic molecules across the blood–brain barrier (BBB) represents a breakthrough in the development of tools for the treatment of many central nervous system (CNS)-associated diseases. The BBB, while being protective against infectious agents, hinders the brain uptake of many
[...] Read more.
The capacity to transport therapeutic molecules across the blood–brain barrier (BBB) represents a breakthrough in the development of tools for the treatment of many central nervous system (CNS)-associated diseases. The BBB, while being protective against infectious agents, hinders the brain uptake of many drugs. Hence, finding safe shuttles able to overcome the BBB is of utmost importance. Herein, we identify a new BBB-translocating peptide with unique properties. For years it was thought that cationic sequences were mandatory for a cell-penetrating peptide (CPP) to achieve cellular internalization. Despite being anionic at physiological pH, PepNeg (sequence (SGTQEEY) is an efficient BBB translocator that is able to carry a large cargo (27 kDa), while maintaining BBB integrity. In addition, PepNeg is able to use two distinct methods of translocation, energy-dependent and -independent, suggesting that direct penetration might occur when low concentrations of peptide are presented to cells. The discovery of this new anionic trans-BBB peptide allows the development of new delivery systems to the CNS and contributes to the need to rethink the role of electrostatic attraction in BBB-translocation. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle Efficacy of Bioactive Cyclic Peptides in Rheumatoid Arthritis: Translation from In Vitro to In Vivo Models
Molecules 2017, 22(10), 1613; doi:10.3390/molecules22101613
Received: 10 August 2017 / Accepted: 15 September 2017 / Published: 25 September 2017
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Abstract
Using a novel drug discovery technology reported in previous issues of this journal cyclic peptides have been created which are able to down-regulate secretion of inflammatory cytokines, in vitro, by stimulated cells of the macrophage cell line J774. The cytokines in question,
[...] Read more.
Using a novel drug discovery technology reported in previous issues of this journal cyclic peptides have been created which are able to down-regulate secretion of inflammatory cytokines, in vitro, by stimulated cells of the macrophage cell line J774. The cytokines in question, TNF-alpha and IL-6, are strongly implicated in etiology of diseases such as rheumatoid arthritis. Studies are reported here using the CAIA animal model for rheumatoid arthritis, which show that the peptides identified are indeed able to impact on inflammation of joints, induced in vivo. The results suggest that these peptides are effective at a dose which could be viable in man, and at which no adverse side effects are evident in the short term. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle The Small Glutathione Peroxidase Mimic 5P May Represent a New Strategy for the Treatment of Liver Cancer
Molecules 2017, 22(9), 1495; doi:10.3390/molecules22091495
Received: 19 July 2017 / Revised: 4 September 2017 / Accepted: 5 September 2017 / Published: 8 September 2017
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Abstract
Glutathione peroxidase (GPx) is an antioxidant protein containing selenium. Owing to the limitations of native GPx, considerable efforts have been made to develop GPx mimics. Here, a short 5-mer peptides (5P) was synthesized and characterized using matrix-assisted laser desorption ionization time-of-flight mass spectrometry.
[...] Read more.
Glutathione peroxidase (GPx) is an antioxidant protein containing selenium. Owing to the limitations of native GPx, considerable efforts have been made to develop GPx mimics. Here, a short 5-mer peptides (5P) was synthesized and characterized using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Enzyme coupled assays were used to evaluate GPx activity. The cell viability and apoptosis of H22 cells were tested, and mice bearing H22 cell-derived tumors were used to determine the effects of 5P on tumor inhibition. In comparison with other enzyme models, 5P provided a suitable substrate with proper catalytic site positions, resulting in enhanced catalytic activity. In our mouse model, 5P showed excellent inhibition of tumor growth and improved immunity. In summary, our findings demonstrated the design and synthesis of the small 5P molecule, which inhibited tumor growth and improved immunity. Notably, 5P could inhibit tumor growth without affecting normal growth. Based on these advantages, the novel mimic may have several clinical applications. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle Preclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic Infection Imaging Agent
Molecules 2017, 22(9), 1403; doi:10.3390/molecules22091403
Received: 30 May 2017 / Accepted: 18 August 2017 / Published: 24 August 2017
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Abstract
The study assessed a radiolabeled depsipeptide conjugate (68Ga-DOTA-TBIA101) for its potential as an imaging agent targeting infection or infection-associated inflammation. 68Ga-labeled DOTA-TBIA101 imaging was performed in (NZR1) healthy rabbits; (NZR2) rabbits bearing muscular sterile inflammation and Staphylococcus aureus (SA) infection;
[...] Read more.
The study assessed a radiolabeled depsipeptide conjugate (68Ga-DOTA-TBIA101) for its potential as an imaging agent targeting infection or infection-associated inflammation. 68Ga-labeled DOTA-TBIA101 imaging was performed in (NZR1) healthy rabbits; (NZR2) rabbits bearing muscular sterile inflammation and Staphylococcus aureus (SA) infection; and (NZR3) rabbits infected with Mycobacterium tuberculosis (MTB) combined with a subcutaneous scruff infection of SA in the same animal. All animals were imaged using a PET/CT scanner at 5 and 60 min post injection. Images showed elevated accumulation of 68Ga-DOTA-TBIA101 in the sterile muscular inflammation site (T/NT ratio = 2.6 ± 0.37 (5 min) and 2.8 ± 2.3 (60 min)) and muscles infected with MTB (T/NT ratio = 2.6 ± 0.35 (5 min) and 2.8 ± 0.16 (60 min)). The findings suggest that 68Ga-DOTA-TBIA101-PET/CT may detect MTB-associated inflammation, although more foundational studies need to be performed to rationalize the diagnostic value of this technique. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine
Molecules 2017, 22(8), 1322; doi:10.3390/molecules22081322
Received: 26 July 2017 / Revised: 4 August 2017 / Accepted: 5 August 2017 / Published: 10 August 2017
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Abstract
One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery
[...] Read more.
One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine. The activation of all gemcitabine prodrugs was faster in pancreatic cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. All prodrugs exhibited great stability in HFF cell homogenate, enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase, and deamination by cytidine deaminase compared to their parent drug. All gemcitabine prodrugs exhibited higher uptake in HFF cells and better permeability across HFF monolayers than gemcitabine, suggesting a better delivery to tumor sites. Cell antiproliferative assays in Panc-1 and Capan-2 pancreatic ductal cell lines indicated that the gemcitabine prodrugs were more potent than their parent drug gemcitabine. The transport and enzymatic profiles of gemcitabine prodrugs suggest their potential for delayed enzymatic bioconversion and enhanced resistance to metabolic enzymes, as well as for enhanced drug delivery to tumor sites, and cytotoxic activity in cancer cells. These attributes would facilitate the prolonged systemic circulation and improved therapeutic efficacy of gemcitabine prodrugs. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessCommunication Antiviral Lipopeptide-Cell Membrane Interaction Is Influenced by PEG Linker Length
Molecules 2017, 22(7), 1190; doi:10.3390/molecules22071190
Received: 21 June 2017 / Revised: 8 July 2017 / Accepted: 13 July 2017 / Published: 15 July 2017
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Abstract
A set of lipopeptides was recently reported for their broad-spectrum antiviral activity against viruses belonging to the Paramyxoviridae family, including human parainfluenza virus type 3 and Nipah virus. Among them, the peptide with a 24-unit PEG linker connecting it to a cholesterol moiety
[...] Read more.
A set of lipopeptides was recently reported for their broad-spectrum antiviral activity against viruses belonging to the Paramyxoviridae family, including human parainfluenza virus type 3 and Nipah virus. Among them, the peptide with a 24-unit PEG linker connecting it to a cholesterol moiety (VG-PEG24-Chol) was found to be the best membrane fusion inhibitory peptide. Here, we evaluated the interaction of the same set of peptides with biomembrane model systems and isolated human peripheral blood mononuclear cells (PBMC). VG-PEG24-Chol showed the highest insertion rate and it was among the peptides that induced a larger change on the surface pressure of cholesterol rich membranes. This peptide also displayed a high affinity towards PBMC membranes. These data provide new information about the dynamics of peptide-membrane interactions of a specific group of antiviral peptides, known for their potential as multipotent paramyxovirus antivirals. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor
Molecules 2017, 22(7), 1189; doi:10.3390/molecules22071189
Received: 8 June 2017 / Revised: 12 July 2017 / Accepted: 12 July 2017 / Published: 15 July 2017
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Abstract
Linear and cyclic analogues of the α-melanocyte stimulating hormone (α-MSH) targeting the human melanocortin receptor 1 (MC1R) are of pharmacological interest for detecting and treating melanoma. The central sequence of α-MSH (His-Phe-Arg-Trp) has been identified as being essential for receptor binding. To deepen
[...] Read more.
Linear and cyclic analogues of the α-melanocyte stimulating hormone (α-MSH) targeting the human melanocortin receptor 1 (MC1R) are of pharmacological interest for detecting and treating melanoma. The central sequence of α-MSH (His-Phe-Arg-Trp) has been identified as being essential for receptor binding. To deepen current knowledge on the molecular basis for α-MSH bioactivity, we aimed to understand the effect of cycle size on receptor binding. To that end, we synthesised two macrocyclic isomeric α-MSH analogues, c[NH-NO2-C6H3-CO-His-DPhe-Arg-Trp-Lys]-Lys-NH2 (CycN-K6) and c[NH-NO2-C6H3-CO-His-DPhe-Arg-Trp-Lys-Lys]-NH2 (CycN-K7). Their affinities to MC1R receptor were determined by competitive binding assays, and their structures were analysed by 1H and 13C NMR. These results were compared to those of the previously reported analogue c[S-NO2-C6H3-CO-His-DPhe-Arg-Trp-Cys]-Lys-NH2 (CycS-C6). The MC1R binding affinity of the 22-membered macrocyclic peptide CycN-K6 (IC50 = 155 ± 16 nM) is higher than that found for the 25-membered macrocyclic analogue CycN-K7 (IC50 = 495 ± 101 nM), which, in turn, is higher than that observed for the 19-membered cyclic analogue CycS-C6 (IC50 = 1770 ± 480 nM). NMR structural study indicated that macrocycle size leads to changes in the relative dispositions of the side chains, particularly in the packing of the Arg side chain relative to the aromatic rings. In contrast to the other analogues, the 22-membered cycle’s side chains are favorably positioned for receptor interaction. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle Characterization of Polyelectrolyte Complex Formation Between Anionic and Cationic Poly(amino acids) and Their Potential Applications in pH-Dependent Drug Delivery
Molecules 2017, 22(7), 1089; doi:10.3390/molecules22071089
Received: 28 April 2017 / Revised: 15 June 2017 / Accepted: 27 June 2017 / Published: 30 June 2017
Cited by 1 | PDF Full-text (1744 KB) | HTML Full-text | XML Full-text
Abstract
Polyelectrolyte complexes (PECs) are self-assembling nano-sized constructs that offer several advantages over traditional nanoparticle carriers including controllable size, biodegradability, biocompatibility, and lack of toxicity, making them particularly appealing as tools for drug delivery. Here, we discuss potential application of PECs for drug delivery
[...] Read more.
Polyelectrolyte complexes (PECs) are self-assembling nano-sized constructs that offer several advantages over traditional nanoparticle carriers including controllable size, biodegradability, biocompatibility, and lack of toxicity, making them particularly appealing as tools for drug delivery. Here, we discuss potential application of PECs for drug delivery to the slightly acidic tumor microenvironment, a pH in the range of 6.5–7.0. Poly(l-glutamic acid) (En), poly(l-lysine) (Kn), and a copolymer composed of histidine-glutamic acid repeats ((HE)n) were studied for their ability to form PECs, which were analyzed for size, polydispersity, and pH sensitivity. PECs showed concentration dependent size variation at residue lengths of E51/K55 and E135/K127, however, no complexes were observed when E22 or K21 were used, even in combination with the longer chains. (HE)20/K55 PECs could encapsulate daunomycin, were stable from pH 7.4–6.5, and dissociated completely between pH 6.5–6.0. Conversely, the E51-dauno/K55 PEC dissociated between pH 4.0 and 3.0. These values for pH-dependent particle dissociation are consistent with the pKa’s of the ionizable groups in each formulation and indicate that the specific pH-sensitivity of (HE)20-dauno/K55 PECs is mediated by incorporation of histidine. This response within a pH range that is physiologically relevant to the acidic tumors suggests a potential application of these PECs in pH-dependent drug delivery. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle Rational Design of Cyclic Antimicrobial Peptides Based on BPC194 and BPC198
Molecules 2017, 22(7), 1054; doi:10.3390/molecules22071054
Received: 29 May 2017 / Revised: 20 June 2017 / Accepted: 22 June 2017 / Published: 24 June 2017
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Abstract
A strategy for the design of antimicrobial cyclic peptides derived from the lead compounds c(KKLKKFKKLQ) (BPC194) and c(KLKKKFKKLQ) (BPC198) is reported. First, the secondary β-structure of BPC194 and BPC198 was analyzed by carrying out molecular dynamics (MD) simulations. Then,
[...] Read more.
A strategy for the design of antimicrobial cyclic peptides derived from the lead compounds c(KKLKKFKKLQ) (BPC194) and c(KLKKKFKKLQ) (BPC198) is reported. First, the secondary β-structure of BPC194 and BPC198 was analyzed by carrying out molecular dynamics (MD) simulations. Then, based on the sequence pattern and the β-structure of BPC194 or BPC198, fifteen analogues were designed and synthesized on solid-phase. The best peptides (BPC490, BPC918, and BPC924) showed minimum inhibitory concentration (MIC) values <6.2 μM against Pseudomonas syringae pv. syringae and Xanthomonas axonopodis pv. vesicatoria, and an MIC value of 12.5 to 25 μM against Erwinia amylovora, being as active as BPC194 and BPC198. Interestingly, these three analogues followed the structural pattern defined from the MD simulations of the parent peptides. Thus, BPC490 maintained the parallel alignment of the hydrophilic pairs K1–K8, K2–K7, and K4–K5, whereas BPC918 and BPC924 included the two hydrophilic interactions K3–Q10 and K5–K8. In short, MD simulations have proved to be very useful for ascertaining the structural features of cyclic peptides that are crucial for their biological activity. Such approaches could be further employed for the development of new antibacterial cyclic peptides. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle The Antiproliferative Effect of Cyclodipeptides from Pseudomonas aeruginosa PAO1 on HeLa Cells Involves Inhibition of Phosphorylation of Akt and S6k Kinases
Molecules 2017, 22(6), 1024; doi:10.3390/molecules22061024
Received: 29 May 2017 / Revised: 14 June 2017 / Accepted: 16 June 2017 / Published: 20 June 2017
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Abstract
Pseudomonas aeruginosa PAO1, a potential pathogen of plants and animals, produces the cyclodipeptides cyclo(l-Pro-l-Tyr), cyclo(l-Pro-l-Phe), and cyclo(l-Pro-l-Val) (PAO1-CDPs), whose effects have been implicated in inhibition of human tumor cell line proliferation. Our purpose was to investigate in depth in the mechanisms of HeLa
[...] Read more.
Pseudomonas aeruginosa PAO1, a potential pathogen of plants and animals, produces the cyclodipeptides cyclo(l-Pro-l-Tyr), cyclo(l-Pro-l-Phe), and cyclo(l-Pro-l-Val) (PAO1-CDPs), whose effects have been implicated in inhibition of human tumor cell line proliferation. Our purpose was to investigate in depth in the mechanisms of HeLa cell proliferation inhibition by the PAO1-CDPs. The results indicate that PAO1-CDPs, both purified individually and in mixtures, inhibited HeLa cell proliferation by arresting the cell cycle at the G0–G1 transition. The crude PAO1-CDPs mixture promoted cell death in HeLa cells in a dose-dependent manner, showing efficacy similar to that of isolated PAO1-CDPs (LD50 of 60–250 µM) and inducing apoptosis with EC50 between 0.6 and 3.0 µM. Moreover, PAO1-CDPs showed a higher proapoptotic activity (~103–105 fold) than their synthetic analogs did. Subsequently, the PAO1-CDPs affected mitochondrial membrane potential and induced apoptosis by caspase-9-dependent pathway. The mechanism of inhibition of cells proliferation in HeLa cells involves inhibition of phosphorylation of both Akt-S473 and S6k-T389 protein kinases, showing a cyclic behavior of their expression and phosphorylation in a time and concentration-dependent fashion. Taken together our findings indicate that PI3K–Akt–mTOR–S6k signaling pathway blockage is involved in the antiproliferative effect of the PAO1-CDPs. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle Antimicrobial Activity of Truncated and Polyvalent Peptides Derived from the FKCRRQWQWRMKKGLA Sequence against Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923
Molecules 2017, 22(6), 987; doi:10.3390/molecules22060987
Received: 29 April 2017 / Revised: 8 June 2017 / Accepted: 12 June 2017 / Published: 14 June 2017
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Abstract
Peptides derived from LfcinB were designed and synthesized, and their antibacterial activity was tested against Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923. Specifically, a peptide library was constructed by systemically removing the flanking residues (N or C-terminal) of Lfcin 17–31 (
[...] Read more.
Peptides derived from LfcinB were designed and synthesized, and their antibacterial activity was tested against Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923. Specifically, a peptide library was constructed by systemically removing the flanking residues (N or C-terminal) of Lfcin 17–31 (17FKCRRWQWRMKKLGA31), maintaining in all peptides the 20RRWQWR25 sequence that corresponds to the minimal antimicrobial motif. For this research, also included were (i) a peptide containing an Ala instead of Cys ([Ala19]-LfcinB 17–31) and (ii) polyvalent peptides containing the RRWQWR sequence and a non-natural amino acid (aminocaproic acid). We established that the lineal peptides LfcinB 17–25 and LfcinB 17–26 exhibited the greatest activity against E. coli ATCC 25922 and S. aureus ATCC 25923, respectively. On the other hand, polyvalent peptides, a dimer and a tetramer, exhibited the greatest antibacterial activity, indicating that multiple copies of the sequence increase the activity. Our results suggest that the dimeric and tetrameric sequence forms potentiate the antibacterial activity of lineal sequences that have exhibited moderate antibacterial activity. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle Screening, Purification and Characterization of Anionic Antimicrobial Proteins from Foeniculum Vulgare
Molecules 2017, 22(4), 602; doi:10.3390/molecules22040602
Received: 2 March 2017 / Revised: 5 April 2017 / Accepted: 6 April 2017 / Published: 8 April 2017
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Abstract
Foeniculum vulgare Mill., commonly called fennel, is a medicinal plant belonging to the Umbelliferae (Apiaceae) family, and is used in traditional medicine. Antibacterial peptides were isolated using sodium phosphate citrate buffer and, for extraction, cetyltrimethyl ammonium bromide (CTAB) buffer with pH 6, have
[...] Read more.
Foeniculum vulgare Mill., commonly called fennel, is a medicinal plant belonging to the Umbelliferae (Apiaceae) family, and is used in traditional medicine. Antibacterial peptides were isolated using sodium phosphate citrate buffer and, for extraction, cetyltrimethyl ammonium bromide (CTAB) buffer with pH 6, have been employed and antimicrobial activity tested against four reference strains. The extracted protein was subjected to 3 kDa dialysis and separation was carried out by DEAE-ion exchange chromatography and further proteins were identified by 2D gel electrophoresis. The results of Foeniculum vulgare elutes obtained from DEAE-ion exchange chromatography were tested for antibacterial activity. Elute 3 shows the highest antibacterial activity on Pseudomonas aeruginosa with a diameter of a zone of inhibition of 16 mm and IC50 value 25.02 (mcg/mL). Based on the findings of the wide usage in treatment of various ailments and day-to-day life, Foeniculum vulgare seeds were used in the present research and have shown promising antibacterial effects, which requires further proteomic research to authenticate the role of the anticipated proteins. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle Synthetic Peptides Derived from Bovine Lactoferricin Exhibit Antimicrobial Activity against E. coli ATCC 11775, S. maltophilia ATCC 13636 and S. enteritidis ATCC 13076
Molecules 2017, 22(3), 452; doi:10.3390/molecules22030452
Received: 7 February 2017 / Revised: 1 March 2017 / Accepted: 8 March 2017 / Published: 12 March 2017
Cited by 3 | PDF Full-text (1181 KB) | HTML Full-text | XML Full-text
Abstract
Linear, dimeric, tetrameric, and cyclic peptides derived from lactoferricin B–containing non-natural amino acids and the RWQWR motif were synthesized, purified, and characterized using RP-HPLC, MALDI-TOF mass spectrometry, and circular dichroism. The antibacterial activity of peptides against Escherichia coli ATCC 11775, Stenotrophomonas maltophilia ATCC
[...] Read more.
Linear, dimeric, tetrameric, and cyclic peptides derived from lactoferricin B–containing non-natural amino acids and the RWQWR motif were synthesized, purified, and characterized using RP-HPLC, MALDI-TOF mass spectrometry, and circular dichroism. The antibacterial activity of peptides against Escherichia coli ATCC 11775, Stenotrophomonas maltophilia ATCC 13636, and Salmonella enteritidis ATCC 13076 was evaluated. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined. The synthetic bovine lactoferricin exhibited antibacterial activity against E. coli ATCC 11775 and S. enteritidis ATCC 13076. The dimeric peptide (RRWQWR)2K-Ahx exhibited the highest antibacterial activity against the tested bacterial strain. The monomeric, cyclic, tetrameric, and palindromic peptides containing the RWQWR motif exhibited high and specific activity against E. coli ATCC 11775. The results suggest that short peptides derived from lactoferricin B could be considered as potential candidates for the development of antibacterial agents against infections caused by E. coli. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessArticle Novel Antihypertensive Peptides Derived from Adlay (Coix larchryma-jobi L. var. ma-yuen Stapf) Glutelin
Molecules 2017, 22(1), 123; doi:10.3390/molecules22010123
Received: 9 October 2016 / Revised: 25 November 2016 / Accepted: 29 December 2016 / Published: 13 January 2017
Cited by 4 | PDF Full-text (1020 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Our previous studies have shown that Coix glutelin pepsin hydrolysate can effectively inhibit angiotensin converting enzyme (ACE) activity in vitro. The main purpose of this study was to obtain potent anti-hypertensive peptides from Coix glutelin. The Coix glutelin hydrolysates (CGH) were prepared by
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Our previous studies have shown that Coix glutelin pepsin hydrolysate can effectively inhibit angiotensin converting enzyme (ACE) activity in vitro. The main purpose of this study was to obtain potent anti-hypertensive peptides from Coix glutelin. The Coix glutelin hydrolysates (CGH) were prepared by pepsin catalysis and further separated by an ultrafitration (UF) system, gel filtration chromatography (GFC) and reversed-phase high performance liquid chromatography (RP-HPLC). As a result, the sub-fraction F5-3 had the highest ACE-inhibitory activity. Six ACE inhibitory peptides were identified using nano-liquid chromatography coupled to tandem mass spectrometry. The most potent peptide GAAGGAF (IC50 = 14.19 μmol·L−1) was finally obtained by further molecular simulation screening and a series of division and optimization. Single oral administration of synthesized GAAGGAF at 15 mg/kg body weight (BW) in spontaneously hypertensive rats (SHR) could reduce the systolic blood pressure (SBP) around 27.50 mmHg and the effect lasted for at least 8 h. The study demonstrated for the first time that the ACE inhibitory peptide GAAGGAF from Coix glutelin has a significant antihypertensive effect, and it could be a good natural ingredient for pharmaceuticals against hypertension and the related diseases. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Review

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Open AccessReview Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity
Molecules 2017, 22(11), 1929; doi:10.3390/molecules22111929
Received: 26 September 2017 / Revised: 31 October 2017 / Accepted: 4 November 2017 / Published: 8 November 2017
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Abstract
Efficient intracellular drug delivery and target specificity are often hampered by the presence of biological barriers. Thus, compounds that efficiently cross cell membranes are the key to improving the therapeutic value and on-target specificity of non-permeable drugs. The discovery of cell-penetrating peptides (CPPs)
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Efficient intracellular drug delivery and target specificity are often hampered by the presence of biological barriers. Thus, compounds that efficiently cross cell membranes are the key to improving the therapeutic value and on-target specificity of non-permeable drugs. The discovery of cell-penetrating peptides (CPPs) and the early design approaches through mimicking the natural penetration domains used by viruses have led to greater efficiency of intracellular delivery. Following these nature-inspired examples, a number of rationally designed CPPs has been developed. In this review, a variety of CPP designs will be described, including linear and flexible, positively charged and often amphipathic CPPs, and more rigid versions comprising cyclic, stapled, or dimeric and/or multivalent, self-assembled peptides or peptido-mimetics. The application of distinct design strategies to known physico-chemical properties of CPPs offers the opportunity to improve their penetration efficiency and/or internalization kinetics. This led to increased design complexity of new CPPs that does not always result in greater CPP activity. Therefore, the transition of CPPs to a clinical setting remains a challenge also due to the concomitant involvement of various internalization routes and heterogeneity of cells used in the in vitro studies. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessReview Wound-Healing Peptides for Treatment of Chronic Diabetic Foot Ulcers and Other Infected Skin Injuries
Molecules 2017, 22(10), 1743; doi:10.3390/molecules22101743
Received: 29 August 2017 / Revised: 6 October 2017 / Accepted: 12 October 2017 / Published: 18 October 2017
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Abstract
As the incidence of diabetes continues to increase in the western world, the prevalence of chronic wounds related to this condition continues to be a major focus of wound care research. Additionally, over 50% of chronic wounds exhibit signs and symptoms that are
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As the incidence of diabetes continues to increase in the western world, the prevalence of chronic wounds related to this condition continues to be a major focus of wound care research. Additionally, over 50% of chronic wounds exhibit signs and symptoms that are consistent with localized bacterial biofilms underlying severe infections that contribute to tissue destruction, delayed wound-healing and other serious complications. Most current biomedical approaches for advanced wound care aim at providing antimicrobial protection to the open wound together with a matrix scaffold (often collagen-based) to boost reestablishment of the skin tissue. Therefore, the present review is focused on the efforts that have been made over the past years to find peptides possessing wound-healing properties, towards the development of new and effective wound care treatments for diabetic foot ulcers and other skin and soft tissue infections. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessReview Toxicity Effects of Functionalized Quantum Dots, Gold and Polystyrene Nanoparticles on Target Aquatic Biological Models: A Review
Molecules 2017, 22(9), 1439; doi:10.3390/molecules22091439
Received: 27 July 2017 / Revised: 17 August 2017 / Accepted: 28 August 2017 / Published: 31 August 2017
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Abstract
Nano-based products are widespread in several sectors, including textiles, medical-products, cosmetics, paints and plastics. Nanosafety and safe-by-design are driving nanoparticle (NP) production and applications through NP functionalization (@NPs). Indeed, @NPs frequently present biological effects that differ from the parent material. This paper reviews
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Nano-based products are widespread in several sectors, including textiles, medical-products, cosmetics, paints and plastics. Nanosafety and safe-by-design are driving nanoparticle (NP) production and applications through NP functionalization (@NPs). Indeed, @NPs frequently present biological effects that differ from the parent material. This paper reviews the impact of quantum dots (QDs), gold nanoparticles (AuNPs), and polystyrene-cored NPs (PSNPs), evidencing the role of NP functionalization in toxicity definition. Key biological models were taken into consideration for NP evaluation: Saccharomyces cerevisiae, fresh- (F) and saltwater (S) microalgae (Raphidocelis subcapitata (F), Scenedesmus obliquus (F) and Chlorella spp. (F), and Phaeodactylum tricornutum (S)), Daphnia magna, and Xenopus laevis. QDs are quite widespread in technological devices, and they are known to induce genotoxicity and oxidative stress that can drastically change according to the coating employed. For example, AuNPs are frequently functionalized with antimicrobial peptides, which is shown to both increase their activity and decrease the relative environmental toxicity. P-NPs are frequently coated with NH2 for cationic and COOH for anionic surfaces, but when positively charged toxicity effects can be observed. Careful assessment of functionalized and non-functionalized NPs is compulsory to also understand their potential direct and indirect effects when the coating is removed or degraded. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
Open AccessReview Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs
Molecules 2017, 22(9), 1430; doi:10.3390/molecules22091430
Received: 11 July 2017 / Revised: 18 August 2017 / Accepted: 22 August 2017 / Published: 29 August 2017
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Abstract
The rapid emergence of multidrug-resistant pathogens has evolved into a global health problem as current treatment options are failing for infections caused by pan-resistant bacteria. Hence, novel antibiotics are in high demand, and for this reason antimicrobial peptides (AMPs) have attracted considerable interest,
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The rapid emergence of multidrug-resistant pathogens has evolved into a global health problem as current treatment options are failing for infections caused by pan-resistant bacteria. Hence, novel antibiotics are in high demand, and for this reason antimicrobial peptides (AMPs) have attracted considerable interest, since they often show broad-spectrum activity, fast killing and high cell selectivity. However, the therapeutic potential of natural AMPs is limited by their short plasma half-life. Antimicrobial peptidomimetics mimic the structure and biological activity of AMPs, but display extended stability in the presence of biological matrices. In the present review, focus is on the developments reported in the last decade with respect to their design, synthesis, antimicrobial activity, cytotoxic side effects as well as their potential applications as anti-infective agents. Specifically, only peptidomimetics with a modular structure of residues connected via amide linkages will be discussed. These comprise the classes of α-peptoids (N-alkylated glycine oligomers), β-peptoids (N-alkylated β-alanine oligomers), β3-peptides, α/β3-peptides, α-peptide/β-peptoid hybrids, α/γ N-acylated N-aminoethylpeptides (AApeptides), and oligoacyllysines (OAKs). Such peptidomimetics are of particular interest due to their potent antimicrobial activity, versatile design, and convenient optimization via assembly by standard solid-phase procedures. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessReview Immuno-Stimulatory Peptides as a Potential Adjunct Therapy against Intra-Macrophagic Pathogens
Molecules 2017, 22(8), 1297; doi:10.3390/molecules22081297
Received: 14 July 2017 / Revised: 3 August 2017 / Accepted: 3 August 2017 / Published: 4 August 2017
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Abstract
The treatment of infectious diseases is increasingly prone to failure due to the rapid spread of antibiotic-resistant pathogens. Antimicrobial peptides (AMPs) are natural components of the innate immune system of most living organisms. Their capacity to kill microbes through multiple mechanisms makes the
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The treatment of infectious diseases is increasingly prone to failure due to the rapid spread of antibiotic-resistant pathogens. Antimicrobial peptides (AMPs) are natural components of the innate immune system of most living organisms. Their capacity to kill microbes through multiple mechanisms makes the development of bacterial resistance less likely. Additionally, AMPs have important immunomodulatory effects, which critically contribute to their role in host defense. In this paper, we review the most recent evidence for the importance of AMPs in host defense against intracellular pathogens, particularly intra-macrophagic pathogens, such as mycobacteria. Cathelicidins and defensins are reviewed in more detail, due to the abundance of studies on these molecules. The cell-intrinsic as well as the systemic immune-related effects of the different AMPs are discussed. In the face of the strong potential emerging from the reviewed studies, the prospects for future use of AMPs as part of the therapeutic armamentarium against infectious diseases are presented. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
Open AccessReview New Insights in the Design of Bioactive Peptides and Chelating Agents for Imaging and Therapy in Oncology
Molecules 2017, 22(8), 1282; doi:10.3390/molecules22081282
Received: 30 May 2017 / Accepted: 25 July 2017 / Published: 2 August 2017
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Abstract
Many synthetic peptides have been developed for diagnosis and therapy of human cancers based on their ability to target specific receptors on cancer cell surface or to penetrate the cell membrane. Chemical modifications of amino acid chains have significantly improved the biological activity,
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Many synthetic peptides have been developed for diagnosis and therapy of human cancers based on their ability to target specific receptors on cancer cell surface or to penetrate the cell membrane. Chemical modifications of amino acid chains have significantly improved the biological activity, the stability and efficacy of peptide analogues currently employed as anticancer drugs or as molecular imaging tracers. The stability of somatostatin, integrins and bombesin analogues in the human body have been significantly increased by cyclization and/or insertion of non-natural amino acids in the peptide sequences. Moreover, the overall pharmacokinetic properties of such analogues and others (including cholecystokinin, vasoactive intestinal peptide and neurotensin analogues) have been improved by PEGylation and glycosylation. Furthermore, conjugation of those peptide analogues to new linkers and bifunctional chelators (such as AAZTA, TETA, TRAP, NOPO etc.), produced radiolabeled moieties with increased half life and higher binding affinity to the cognate receptors. This review describes the most important and recent chemical modifications introduced in the amino acid sequences as well as linkers and new bifunctional chelators which have significantly improved the specificity and sensitivity of peptides used in oncologic diagnosis and therapy. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessReview Cyclic Peptides as Novel Therapeutic Microbicides: Engineering of Human Defensin Mimetics
Molecules 2017, 22(7), 1217; doi:10.3390/molecules22071217
Received: 28 June 2017 / Revised: 17 July 2017 / Accepted: 18 July 2017 / Published: 20 July 2017
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Abstract
Cyclic peptides are receiving significant attention thanks to their antimicrobial activity and high serum stability, which is useful to develop and design novel antimicrobial agents. Antimicrobial peptides appear to be key components of innate defences against bacteria, viruses, and fungi. Among the others,
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Cyclic peptides are receiving significant attention thanks to their antimicrobial activity and high serum stability, which is useful to develop and design novel antimicrobial agents. Antimicrobial peptides appear to be key components of innate defences against bacteria, viruses, and fungi. Among the others, defensins possess a strong microbicidial activity. Defensins are cationic and amphipathic peptides with six cysteine residues connected by three disulfide bonds found in plants, insects, and mammals; they are divided in three families: α-, β-, and θ-defensins. α-Defensins are contained in the primary granules of human neutrophils; β-defensins are expressed in human epithelia; and θ-defensins are pseudo-cyclic defensins not found in humans, but in rhesus macaques. The structural diversities among the three families are reflected in a different antimicrobial action as well as in serum stability. The engineering of these peptides is an exciting opportunity to obtain more functional antimicrobial molecules highlighting their potential as therapeutic agents. The present review reports the most recent advances in the field of cyclic peptides with a specific regard to defensin analogs. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Open AccessReview β-Defensins in the Fight against Helicobacter pylori
Molecules 2017, 22(3), 424; doi:10.3390/molecules22030424
Received: 5 January 2017 / Accepted: 4 March 2017 / Published: 7 March 2017
Cited by 3 | PDF Full-text (1032 KB) | HTML Full-text | XML Full-text
Abstract
Antimicrobial peptides (AMPs) play a pivotal role in the innate immune responses to Helicobacter pylori (Hp) in humans. β-Defensins, a class of cationic arginine-rich AMPs, are small peptides secreted by immune cells and epithelial cells that exert antimicrobial activity against a broad spectrum
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Antimicrobial peptides (AMPs) play a pivotal role in the innate immune responses to Helicobacter pylori (Hp) in humans. β-Defensins, a class of cationic arginine-rich AMPs, are small peptides secreted by immune cells and epithelial cells that exert antimicrobial activity against a broad spectrum of microorganisms, including Gram-positive and Gram-negative bacteria and fungi. During Hp infections, AMP expression is able to eradicate the bacteria, thereby preventing Hp infections in gastrointestinal tract. It is likely that gastric β-defensins expression is increased during Hp infection. The aim of this review is to focus on increased knowledge of the role of β-defensins in response to Hp infection. We also briefly discuss the potential use of AMPs, either alone or in combination with conventional antibiotics, for the treatment of Hp infection. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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