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Chemical Functionalization of Bioactive Peptides

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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 18506

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Dr. Elio Pizzo

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Guest Editor

Department of Biology, University of Naples 'Federico II', Naples, Italy
Interests: bioactive peptides; immunomodulatory agents; natural products; toxins; anti-cancer proteins

Special Issue Information

Dear Colleagues,

Peptides are small amino acid polymers involved in a number of processes. Recently, great attention has been focused on studying the bioactive roles of peptides, such as antimicrobial, antithrombotic, antihypertensive, opioid, immunomodulatory, mineral binding, and antioxidative effect. The function that a bioactive peptide carries out is dependent on the types of amino acids involved in the chain and their sequence, as well as the specific shape of the peptide when it interacts with its target. In this framework, any possible chemical modifications designed to probe the structure, function, and stability of a bioactive peptide, intriguingly represent a strong incentive in various application fields.

This Special Issue covers all possible chemical modifications on bioactive peptides, natural or synthetic, designed with the aim to improve their natural propensity or even to induce new properties. In this regard, this Special Issue is focused on modified peptides in which the peptide character is still preponderant, with a particular emphasis on the chemical methodologies utilized to introduce these modifications. In addition, research articles and reviews related to recent findings about chemical modification procedures will be also included, whereby the native structure of a peptide is specifically tailored to acquire ancillary features to support its biological properties.

Dr. Elio Pizzo
Guest Editor

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Keywords

Protease stability
Unnatural amino acid
De novo design
Labeling
Protecting groups
Sidechain modification
Glycosylation
Lipidation

Published Papers (4 papers)

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Research

32 pages, 9359 KiB

Open AccessArticle

Cyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca²⁺ Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential

by Chandrasekar Balachandran, Kenta Yokoi, Kana Naito, Jebiti Haribabu, Yuichi Tamura, Masakazu Umezawa, Koji Tsuchiya, Toshitada Yoshihara, Seiji Tobita and Shin Aoki

Molecules 2021, 26(22), 7028; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26227028 - 21 Nov 2021

Cited by 16 | Viewed by 2885

Abstract

In our previous paper, we reported that amphiphilic Ir complex–peptide hybrids (IPHs) containing basic peptides such as KK(K)GG (K: lysine, G: glycine) (e.g., ASb-2) exhibited potent anticancer activity against Jurkat cells, with the dead cells showing a strong green emission. Our initial mechanistic studies of this cell death suggest that IPHs would bind to the calcium (Ca²⁺)–calmodulin (CaM) complex and induce an overload of intracellular Ca²⁺, resulting in the induction of non-apoptotic programmed cell death. In this work, we conduct a detailed mechanistic study of cell death induced by ASb-2, a typical example of IPHs, and describe how ASb-2 induces paraptotic programmed cell death in a manner similar to that of celastrol, a naturally occurring triterpenoid that is known to function as a paraptosis inducer in cancer cells. It is suggested that ASb-2 (50 µM) induces ER stress and decreases the mitochondrial membrane potential (ΔΨ_m), thus triggering intracellular signaling pathways and resulting in cytoplasmic vacuolization in Jurkat cells (which is a typical phenomenon of paraptosis), while the change in ΔΨ_m values is negligibly induced by celastrol and curcumin. Other experimental data imply that both ASb-2 and celastrol induce paraptotic cell death in Jurkat cells, but this induction occurs via different signaling pathways. Full article

(This article belongs to the Special Issue Chemical Functionalization of Bioactive Peptides)

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15 pages, 4081 KiB

Open AccessArticle

Synthetic Peptide ΔM4-Induced Cell Death Associated with Cytoplasmic Membrane Disruption, Mitochondrial Dysfunction and Cell Cycle Arrest in Human Melanoma Cells

by Gloria A. Santa-González, Edwin Patiño-González and Marcela Manrique-Moreno

Molecules 2020, 25(23), 5684; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25235684 - 02 Dec 2020

Cited by 8 | Viewed by 2003

Abstract

Melanoma is the most dangerous and lethal form of skin cancer, due to its ability to spread to different organs if it is not treated at an early stage. Conventional chemotherapeutics are failing as a result of drug resistance and weak tumor selectivity. Therefore, efforts to evaluate novel molecules for the treatment of skin cancer are necessary. Antimicrobial peptides have become attractive anticancer agents because they execute their biological activity with features such as a high potency of action, a wide range of targets, and high target specificity and selectivity. In the present study, the antiproliferative activity of the synthetic peptide ΔM4 on A375 human melanoma cells and spontaneously immortalized HaCaT human keratinocytes was investigated. The cytotoxic effect of ΔM4 treatment was evaluated through propidium iodide uptake by flow cytometry. The results indicated selective toxicity in A375 cells and, in order to further investigate the mode of action, assays were carried out to evaluate morphological changes, mitochondrial function, and cell cycle progression. The findings indicated that ΔM4 exerts its antitumoral effects by multitarget action, causing cell membrane disruption, a change in the mitochondrial transmembrane potential, an increase of reactive oxygen species, and cell cycle accumulation in S-phase. Further exploration of the peptide may be helpful in the design of novel anticancer peptides. Full article

(This article belongs to the Special Issue Chemical Functionalization of Bioactive Peptides)

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12 pages, 3068 KiB

Open AccessArticle

Recombinant Expression and Stapling of a Novel Long-Acting GLP-1R Peptide Agonist

by Sam Lear, Hyosuk Seo, Candy Lee, Lei Lei, Zaid Amso, David Huang, Huafei Zou, Zhihong Zhou, Vân T. B. Nguyen-Tran and Weijun Shen

Molecules 2020, 25(11), 2508; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25112508 - 28 May 2020

Cited by 2 | Viewed by 5571

Abstract

Owing to their pleiotropic metabolic benefits, glucagon-like peptide-1 receptor (GLP-1R) agonists have been successfully utilized for treating metabolic diseases, such as type 2 diabetes and obesity. As part of our efforts in developing long-acting peptide therapeutics, we have previously reported a peptide engineering strategy that combines peptide side chain stapling with covalent integration of a serum protein-binding motif in a single step. Herein, we have used this strategy to develop a second generation extendin-4 analog rigidified with a symmetrical staple, which exhibits an excellent in vivo efficacy in an animal model of diabetes and obesity. To simplify the scale-up manufacturing of the lead GLP-1R agonist, a semisynthesis protocol was successfully developed, which involves recombinant expression of the linear peptide followed by attachment of a polyethylene glycol (PEG)-fatty acid staple in a subsequent chemical reaction step. Full article

(This article belongs to the Special Issue Chemical Functionalization of Bioactive Peptides)

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17 pages, 2551 KiB

Open AccessArticle

AEDG Peptide (Epitalon) Stimulates Gene Expression and Protein Synthesis during Neurogenesis: Possible Epigenetic Mechanism

by Vladimir Khavinson, Francesca Diomede, Ekaterina Mironova, Natalia Linkova, Svetlana Trofimova, Oriana Trubiani, Sergio Caputi and Bruna Sinjari

Molecules 2020, 25(3), 609; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25030609 - 30 Jan 2020

Cited by 15 | Viewed by 7218

Abstract

It was shown that AEDG peptide (Ala-Glu-Asp-Gly, Epitalon) regulates the function of the pineal gland, the retina, and the brain. AEDG peptide increases longevity in animals and decreases experimental cancerogenesis. AEDG peptide induces neuronal cell differentiation in retinal and human periodontal ligament stem cells. The aim of the study was to investigate the influence of AEDG peptide on neurogenic differentiation gene expression and protein synthesis in human gingival mesenchymal stem cells, and to suggest the basis for the epigenetic mechanism of this process. AEDG peptide increased the synthesis of neurogenic differentiation markers: Nestin, GAP43, β Tubulin III, Doublecortin in hGMSCs. AEDG peptide increased Nestin, GAP43, β Tubulin III and Doublecortin mRNA expression by 1.6–1.8 times in hGMSCs. Molecular modelling method showed, that AEDG peptide preferably binds with H1/6 and H1/3 histones in His-Pro-Ser-Tyr-Met-Ala-His-Pro-Ala-Arg-Lys and Tyr-Arg-Lys-Thr-Gln sites, which interact with DNA. These results correspond to previous experimental data. AEDG peptide and histones H1/3, H1/6 binding may be one of the mechanisms which provides an increase of Nestin, GAP43, β Tubulin III, and Doublecortin neuronal differentiation gene transcription. AEDG peptide can epigenetically regulate neuronal differentiation gene expression and protein synthesis in human stem cells. Full article

(This article belongs to the Special Issue Chemical Functionalization of Bioactive Peptides)

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