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Special Issue "Peptide Therapeutics"

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

Deadline for manuscript submissions: closed (10 October 2017)

Special Issue Editors

Guest Editor
Prof. Fernando Albericio

1. School of Chemistry, University of KwaZulu-Natal, Durban 4001, South Africa
2. Department of Organic Chemistry, University of Barcelona, 08028-Barcelona, Spain
Website1 | Website2 | E-Mail
Fax: +34 93 403 71 26
Interests: solid-phase chemistry, combinatorial chemistry, drug delivery systems, peptides, peptide drug conjugates, orthogonal chemistry, drug discovery, biomaterials
Guest Editor
Prof. Beatriz G. de la Torre

School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, 4001 Durban, South Africa
Website | E-Mail
Interests: peptides; solid-phase synthesis; cell penetrating peptides; antimicrobial peptides, oligonucleotides, peptide nucleic acids; drug discovery; peptides drug conjugates

Special Issue Information

Dear Colleagues,

During the last few years, the role of peptides in the drug discovery arena have been increased enormously, and, every year, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approve several of these chemical entities as new drugs. It is interesting to analyze the peptide–amino-acid-based drugs accepted by the FDA in 2016 (Molecules, 22, 368; doi:10.3390/molecules22030368 (2017)). Adlyxin (Lixisenatide) is a 44-amino acid peptide, which can be considered as a small protein prepared by chemical methods, is a glucagon-like peptide (GLP-1). At the opposite end of the complexity point of view, Xiidra (Lifitegrast), which is recommended for dry eye disease, in an acyl dipeptide formed by two non-natural amino acids. During 2016, the FDA approved two amino acid derivatives: Briviact (Brivaracetam) and Auxim (Fluciclovine f-18) for epilepsy and as a diagnostic agent in Positron emission tomography (PET) imaging for cancer. This is an excellent example of the diversity of our field, in terms of both chemical structure and target therapeutics.

However, even more important than the number of chemical entities accepted by agencies is the large number of peptides that are presently in clinical trials. Furthermore, peptides, in addition to being an active pharmaceutical ingredient (API), are being used as shuttles to overcome some barriers, and are also used as linkers to bind together two moieties in the same drug, as occurs in antibody drug conjugates (ADC).

This Special Issue of Molecules aims to reflect the wonderful world surrounding peptides as therapeutics.

Prof. Fernando Albericio
Prof. Beatriz G. de la Torre
Guest Editors

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 papers will be 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. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

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

Keywords

  • therapeutic peptides
  • solid-phase peptide synthesis
  • antimicrobial peptides
  • peptides and Alzheimer disease
  • peptides and metabolic syndrome
  • peptides and cancer
  • peptides as shuttles
  • peptide based drug delivery
  • peptide based vaccines
  • peptides drug conjugates

Published Papers (8 papers)

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Research

Open AccessArticle Adding an Artificial Tail—Anchor to a Peptide-Based HIV-1 Fusion Inhibitor for Improvement of Its Potency and Resistance Profile
Molecules 2017, 22(11), 1996; doi:10.3390/molecules22111996 (registering DOI)
Received: 15 October 2017 / Revised: 10 November 2017 / Accepted: 16 November 2017 / Published: 20 November 2017
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Abstract
Peptides derived from the C-terminal heptad repeat (CHR) of human immunodeficiency virus type 1 (HIV-1) envelope protein transmembrane subunit gp41, such as T20 (enfuvirtide), can bind to the N-terminal heptad repeat (NHR) of gp41 and block six-helix bundle (6-HB) formation, thus inhibiting HIV-1
[...] Read more.
Peptides derived from the C-terminal heptad repeat (CHR) of human immunodeficiency virus type 1 (HIV-1) envelope protein transmembrane subunit gp41, such as T20 (enfuvirtide), can bind to the N-terminal heptad repeat (NHR) of gp41 and block six-helix bundle (6-HB) formation, thus inhibiting HIV-1 fusion with the target cell. However, clinical application of T20 is limited because of its low potency and genetic barrier to resistance. HP23, the shortest CHR peptide, exhibits better anti-HIV-1 activity than T20, but the HIV-1 strains with E49K mutations in gp41 will become resistant to it. Here, we modified HP23 by extending its C-terminal sequence using six amino acid residues (E6) and adding IDL (Ile-Asp-Leu) to the C-terminus of E6, which is expected to bind to the shallow pocket in the gp41 NHR N-terminal region. The newly designed peptide, designated HP23-E6-IDL, was about 2- to 16-fold more potent than HP23 against a broad spectrum of HIV-1 strains and more than 12-fold more effective against HIV-1 mutants resistant to HP23. These findings suggest that addition of an anchor–tail to the C-terminus of a CHR peptide will allow binding with the pocket in the gp41 NHR that may increase the peptide’s antiviral efficacy and its genetic barrier to resistance. Full article
(This article belongs to the Special Issue Peptide Therapeutics)
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Open AccessArticle NeoBOMB1, a GRPR-Antagonist for Breast Cancer Theragnostics: First Results of a Preclinical Study with [67Ga]NeoBOMB1 in T-47D Cells and Tumor-Bearing Mice
Molecules 2017, 22(11), 1950; doi:10.3390/molecules22111950
Received: 26 October 2017 / Revised: 6 November 2017 / Accepted: 8 November 2017 / Published: 11 November 2017
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Abstract
Background: The GRPR-antagonist-based radioligands [67/68Ga/111In/177Lu]NeoBOMB1 have shown excellent theragnostic profiles in preclinical prostate cancer models, while [68Ga]NeoBOMB1 effectively visualized prostate cancer lesions in patients. We were further interested to explore the theragnostic potential of NeoBOMB1
[...] Read more.
Background: The GRPR-antagonist-based radioligands [67/68Ga/111In/177Lu]NeoBOMB1 have shown excellent theragnostic profiles in preclinical prostate cancer models, while [68Ga]NeoBOMB1 effectively visualized prostate cancer lesions in patients. We were further interested to explore the theragnostic potential of NeoBOMB1 in GRPR-positive mammary carcinoma, by first studying [67Ga]NeoBOMB1 in breast cancer models; Methods: We investigated the profile of [67Ga]NeoBOMB1, a [68Ga]NeoBOMB1 surrogate, in GRPR-expressing T-47D cells and animal models; Results: NeoBOMB1 (IC50s of 2.2 ± 0.2 nM) and [natGa]NeoBOMB1 (IC50s of 2.5 ± 0.2 nM) exhibited high affinity for the GRPR. At 37 °C [67Ga]NeoBOMB1 strongly bound to the T-47D cell-membrane (45.8 ± 0.4% at 2 h), internalizing poorly, as was expected for a radioantagonist. [67Ga]NeoBOMB1 was detected >90% intact in peripheral mouse blood at 30 min pi. In mice bearing T-47D xenografts, [67Ga]NeoBOMB1 specifically localized in the tumor (8.68 ± 2.9% ID/g vs. 0.6 ± 0.1% ID/g during GRPR-blockade at 4 h pi). The unfavorably high pancreatic uptake could be considerably reduced (206.29 ± 17.35% ID/g to 42.46 ± 1.31% ID/g at 4 h pi) by increasing the NeoBOMB1 dose from 10 pmol to 200 pmol, whereas tumor uptake remained unaffected. Notably, tumor values did not decline from 1 to 24 h pi; Conclusions: [67Ga]NeoBOMB1 can successfully target GRPR-positive breast cancer in animals with excellent prospects for clinical translation. Full article
(This article belongs to the Special Issue Peptide Therapeutics)
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Open AccessCommunication Non-Covalent Loading of Anti-Cancer Doxorubicin by Modularizable Peptide Self-Assemblies for a Nanoscale Drug Carrier
Molecules 2017, 22(11), 1916; doi:10.3390/molecules22111916
Received: 4 October 2017 / Accepted: 30 October 2017 / Published: 6 November 2017
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Abstract
We prepared nanoscale, modularizable, self-assembled peptide nanoarchitectures with diameters less of than 20 nm by combining β-sheet-forming peptides tethering a cell-penetrating peptide or a nuclear localization signal sequence. We also found that doxorubicin (Dox), an anti-cancer drug, was non-covalently accommodated by the assemblies
[...] Read more.
We prepared nanoscale, modularizable, self-assembled peptide nanoarchitectures with diameters less of than 20 nm by combining β-sheet-forming peptides tethering a cell-penetrating peptide or a nuclear localization signal sequence. We also found that doxorubicin (Dox), an anti-cancer drug, was non-covalently accommodated by the assemblies at a ratio of one Dox molecule per ten peptides. The Dox-loaded peptide assemblies facilitated cellular uptake and subsequent nuclear localization in HeLa cells, and induced cell death even at low Dox concentrations. This peptide nanocarrier motif is a promising platform for a biocompatible drug delivery system by altering the targeting head groups of the carrier peptides. Full article
(This article belongs to the Special Issue Peptide Therapeutics)
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Open AccessArticle Antibacterial Activity of the Non-Cytotoxic Peptide (p-BthTX-I)2 and Its Serum Degradation Product against Multidrug-Resistant Bacteria
Molecules 2017, 22(11), 1898; doi:10.3390/molecules22111898
Received: 3 October 2017 / Revised: 30 October 2017 / Accepted: 31 October 2017 / Published: 4 November 2017
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Abstract
Antimicrobial peptides can be used systemically, however, their susceptibility to proteases is a major obstacle in peptide-based therapeutic development. In the present study, the serum stability of p-BthTX-I (KKYRYHLKPFCKK) and (p-BthTX-I)2, a p-BthTX-I disulfide-linked dimer, were analyzed by mass spectrometry and
[...] Read more.
Antimicrobial peptides can be used systemically, however, their susceptibility to proteases is a major obstacle in peptide-based therapeutic development. In the present study, the serum stability of p-BthTX-I (KKYRYHLKPFCKK) and (p-BthTX-I)2, a p-BthTX-I disulfide-linked dimer, were analyzed by mass spectrometry and analytical high-performance liquid chromatography (HPLC). Antimicrobial activities were assessed by determining their minimum inhibitory concentrations (MIC) using cation-adjusted Mueller–Hinton broth. Furthermore, biofilm eradication and time-kill kinetics were performed. Our results showed that p-BthTX-I and (p-BthTX-I)2 were completely degraded after 25 min. Mass spectrometry showed that the primary degradation product was a peptide that had lost four lysine residues on its C-terminus region (des-Lys12/Lys13-(p-BthTX-I)2), which was stable after 24 h of incubation. The antibacterial activities of the peptides p-BthTX-I, (p-BthTX-I)2, and des-Lys12/Lys13-(p-BthTX-I)2 were evaluated against a variety of bacteria, including multidrug-resistant strains. Des-Lys12/Lys13-(p-BthTX-I)2 and (p-BthTX-I)2 degraded Staphylococcus epidermidis biofilms. Additionally, both the peptides exhibited bactericidal activities against planktonic S. epidermidis in time-kill assays. The emergence of bacterial resistance to a variety of antibiotics used in clinics is the ultimate challenge for microbial infection control. Therefore, our results demonstrated that both peptides analyzed and the product of proteolysis obtained from (p-BthTX-I)2 are promising prototypes as novel drugs to treat multidrug-resistant bacterial infections. Full article
(This article belongs to the Special Issue Peptide Therapeutics)
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Open AccessArticle A Large Size Chimeric Highly Immunogenic Peptide Presents Multistage Plasmodium Antigens as a Vaccine Candidate System against Malaria
Molecules 2017, 22(11), 1837; doi:10.3390/molecules22111837
Received: 20 September 2017 / Revised: 16 October 2017 / Accepted: 23 October 2017 / Published: 1 November 2017
PDF Full-text (3964 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Rational strategies for obtaining malaria vaccine candidates should include not only a proper selection of target antigens for antibody stimulation, but also a versatile molecular design based on ordering the right pieces from the complex pathogen molecular puzzle towards more active and functional
[...] Read more.
Rational strategies for obtaining malaria vaccine candidates should include not only a proper selection of target antigens for antibody stimulation, but also a versatile molecular design based on ordering the right pieces from the complex pathogen molecular puzzle towards more active and functional immunogens. Classical Plasmodium falciparum antigens regarded as vaccine candidates have been selected as model targets in this study. Among all possibilities we have chosen epitopes of PfCSP, STARP; MSA1 and Pf155/RESA from pre- and erythrocyte stages respectively for designing a large 82-residue chimeric immunogen. A number of options aimed at diminishing steric hindrance for synthetic procedures were assessed based on standard Fmoc chemistry such as building block orthogonal ligation; pseudo-proline and microwave-assisted procedures, therefore the large-chimeric target was produced, characterized and immunologically tested. Antigenicity and functional in vivo efficacy tests of the large-chimera formulations administered alone or as antigen mixtures have proven the stimulation of high antibody titers, showing strong correlation with protection and parasite clearance of vaccinated BALB/c mice after being lethally challenged with both P. berghei-ANKA and P. yoelii 17XL malaria strains. Besides, 3D structure features shown by the large-chimera encouraged as to propose using these rational designed large synthetic molecules as reliable vaccine candidate-presenting systems. Full article
(This article belongs to the Special Issue Peptide Therapeutics)
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Open AccessArticle Disrupting VEGF–VEGFR1 Interaction: De Novo Designed Linear Helical Peptides to Mimic the VEGF13-25 Fragment
Molecules 2017, 22(11), 1846; doi:10.3390/molecules22111846
Received: 9 October 2017 / Revised: 20 October 2017 / Accepted: 26 October 2017 / Published: 28 October 2017
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Abstract
The interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFR) has important implications in angiogenesis and cancer, which moved us to search for peptide derivatives able to block this protein–protein interaction. In a previous work we had described a collection of
[...] Read more.
The interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFR) has important implications in angiogenesis and cancer, which moved us to search for peptide derivatives able to block this protein–protein interaction. In a previous work we had described a collection of linear 13-mer peptides specially designed to adopt helical conformations (Ac-SSEEX5ARNX9AAX12N-NH2), as well as the evaluation of seven library components for the inhibition of the interaction of VEGF with its Receptor 1 (VEGFR1). This study led to the discovery of some new, quite potent inhibitors of this protein–protein system. The results we found prompted us to extend the study to other peptides of the library. We describe here the evaluation of a new selection of peptides from the initial library that allow us to identify new VEGF-VEGFR1 inhibitors. Among them, the peptide sequence containing F, W, and I residues at the 5, 9, and 12 positions, show a very significant nanomolar IC50 value, competing with VEGF for its receptor 1, VEGFR1 (Flt-1), which could represent a new tool within the therapeutic arsenal for cancer detection and therapy. Full article
(This article belongs to the Special Issue Peptide Therapeutics)
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Open AccessArticle Antibacterial Synthetic Peptides Derived from Bovine Lactoferricin Exhibit Cytotoxic Effect against MDA-MB-468 and MDA-MB-231 Breast Cancer Cell Lines
Molecules 2017, 22(10), 1641; doi:10.3390/molecules22101641
Received: 8 September 2017 / Revised: 27 September 2017 / Accepted: 28 September 2017 / Published: 29 September 2017
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Abstract
Linear, dimeric, tetrameric, and cyclic peptides derived from lactoferricin B, containing the RRWQWR motif, were designed, synthesized, purified, and characterized using RP-HPLC chromatography and MALDI-TOF mass spectrometry. The antibacterial activity of the designed peptides against E. coli (ATCC 11775 and 25922) and their
[...] Read more.
Linear, dimeric, tetrameric, and cyclic peptides derived from lactoferricin B, containing the RRWQWR motif, were designed, synthesized, purified, and characterized using RP-HPLC chromatography and MALDI-TOF mass spectrometry. The antibacterial activity of the designed peptides against E. coli (ATCC 11775 and 25922) and their cytotoxic effect against MDA-MB-468 and MDA-MB-231 breast cancer cell lines were evaluated. Dimeric and tetrameric peptides showed higher antibacterial activity in both bacteria strains than linear peptides. The dimeric peptide (RRWQWR)2K-Ahx exhibited the highest antibacterial activity against the tested bacterial strains. Furthermore, the peptides with high antibacterial activity exhibited significant cytotoxic effect against the tested breast cancer cell lines. This cytotoxic effect was fast and dependent on the peptide concentration. The tetrameric molecule containing RRWQWR motif has an optimal cytotoxic effect at a concentration of 22 µM. The evaluated dimeric and tetrameric peptides could be considered as candidates for developing new therapeutic agents against breast cancer. Polyvalence of linear sequences could be considered as a novel and versatile strategy for obtaining molecules with high anticancer activity. Full article
(This article belongs to the Special Issue Peptide Therapeutics)
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Open AccessCommunication Investigation of the N-Terminus Amino Function of Arg10-Teixobactin
Molecules 2017, 22(10), 1632; doi:10.3390/molecules22101632
Received: 28 August 2017 / Revised: 24 September 2017 / Accepted: 25 September 2017 / Published: 28 September 2017
Cited by 1 | PDF Full-text (712 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Teixobactin is a recently described antimicrobial peptide that shows high activity against gram-positive bacteria as well as mycobacterium tuberculosis. Due to both its structure as a head-to-side chain cyclodepsipeptide and its activity, it has attracted the attention of several research groups. In
[...] Read more.
Teixobactin is a recently described antimicrobial peptide that shows high activity against gram-positive bacteria as well as mycobacterium tuberculosis. Due to both its structure as a head-to-side chain cyclodepsipeptide and its activity, it has attracted the attention of several research groups. In this regard, a large number of analogs with substitutions in both the cycle and the tail has been described. Here, we report the contribution of the N-terminus residue, N-Me-d-Phe, to the activity of Arg10-teixobactin. On the basis of our findings, we conclude that the N-terminus accepts minimum changes but not the presence of long alkyl chains. The presence of a positive charge is a requirement for the activity of the peptide. Furthermore, acylation of the N-terminus leads to total loss of activity. Full article
(This article belongs to the Special Issue Peptide Therapeutics)
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