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Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 30176

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Dr. Nunzianna Doti

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Guest Editor

Institute of Biostructures and Bioimaging (IBB)-CNR, Via Mezzocannone 16, 80134 Naples, Italy
Interests: peptides; peptidomimetics
Special Issues, Collections and Topics in MDPI journals

Dr. Menotti Ruvo

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Guest Editor

Istituto di Biostrutture e Bioimmagini, CNR, 80134 Napoli, Italy
Interests: monoclonal antibodies; antibody functional fragments; antibody drug conjugates
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Synthetic peptides are gaining increasing interest as both research tools in basic and applied science and as therapeutic and diagnostic agents in clinical settings. Their use as inhibitors of protein–protein interactions is becoming a common practice toward elucidating the binding mode of proteins, advancing our understanding of signaling cascades, and offering a viable contribution to the design and development of new drugs. Synthetic peptides are also ideal ligands for extracellular receptors, acting as potent activators of several cellular pathways such as those of the immune response. To date, about 60 peptides have been approved for human use worldwide, many of which are derived from natural molecules, and hundreds more are progressing through the different stages of clinical trials. However, the poor membrane permeability, short plasma half-life, and scarce oral bioavailability strongly limit their druggability and negatively impact on clinical aspects. In this scenario, novel structural modifications are continuously sought for improving pharmacokinetic properties. Among others, amino acid or backbone modifications and the introduction of non-natural amino acids and conjugation of chemical moieties that extend the half-life, improve cellular uptake, stabilize active conformations, and modulate solubility are constantly proposed. Given the high biocompatibility, generally low toxicity, and functionalization potential, peptides and peptidomimetics are also being increasingly employed to develop new functional biomaterials which are excellent cell culture substrates for medicinal applications or that may act as biorecognition elements for the detection of analytes such as proteins, nucleic acids, and pathogens. In this instance, peptides are also being used as recognition units for chip-based biosensors for clinical diagnosis.

We therefore invite academic and industrial investigators working in all these fields to submit original research articles or reviews describing and discussing the most recent advancements and developments in basic science and biomedical applications.

Potential topics include, but are not limited to:

Synthetic peptides and peptidomimetics as protein–protein inhibitors
Synthetic procedures for preparing peptides and peptidomimetics
Biochemical and biophysical characterization of peptides and peptidomimetics
Peptide-based bioconjugation
Nanoparticle-conjugated peptides
Peptide-based bioreceptors
Peptide-based biomaterials

Dr. Nunzianna Doti
Dr. Menotti Ruvo
Guest Editors

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

4 pages, 155 KiB

Open AccessEditorial

Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—Second Edition

by Nunzianna Doti and Menotti Ruvo

Int. J. Mol. Sci. 2024, 25(2), 1083; https://doi.org/10.3390/ijms25021083 - 16 Jan 2024

Cited by 1 | Viewed by 1507

Abstract

Peptides are increasingly emerging as a drug class for a wide range of human diseases due to their intrinsic properties, such as excellent recognition abilities and biocompatibility [...] Full article

(This article belongs to the Special Issue Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition)

Research

Jump to: Editorial, Review

21 pages, 3920 KiB

Open AccessArticle

Myxinidin-Derived Peptide against Biofilms Caused by Cystic Fibrosis Emerging Pathogens

by Rosa Bellavita, Angela Maione, Simone Braccia, Marica Sinoca, Stefania Galdiero, Emilia Galdiero and Annarita Falanga

Int. J. Mol. Sci. 2023, 24(4), 3092; https://doi.org/10.3390/ijms24043092 - 4 Feb 2023

Cited by 7 | Viewed by 2124

Abstract

Chronic lung infections in cystic fibrosis (CF) patients are triggered by multidrug-resistant bacteria such as Pseudomonas aeruginosa, Achromobacter xylosoxidans, and Stenotrophomonas maltophilia. The CF airways are considered ideal sites for the colonization and growth of bacteria and fungi that favor the formation of mixed biofilms that are difficult to treat. The inefficacy of traditional antibiotics reinforces the need to find novel molecules able to fight these chronic infections. Antimicrobial peptides (AMPs) represent a promising alternative for their antimicrobial, anti-inflammatory, and immunomodulatory activities. We developed a more serum-stable version of the peptide WMR (WMR-4) and investigated its ability to inhibit and eradicate C. albicans, S. maltophilia, and A. xylosoxidans biofilms in both in vitro and in vivo studies. Our results suggest that the peptide is able better to inhibit than to eradicate both mono and dual-species biofilms, which is further confirmed by the downregulation of some genes involved in biofilm formation or in quorum-sensing signaling. Biophysical data help to elucidate its mode of action, showing a strong interaction of WMR-4 with lipopolysaccharide (LPS) and its insertion in liposomes mimicking Gram-negative and Candida membranes. Our results support the promising therapeutic application of AMPs in the treatment of mono- and dual-species biofilms during chronic infections in CF patients. Full article

(This article belongs to the Special Issue Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition)

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19 pages, 1615 KiB

Open AccessArticle

Synthesis and Antimicrobial Activity of Short Analogues of the Marine Antimicrobial Peptide Turgencin A: Effects of SAR Optimizations, Cys-Cys Cyclization and Lipopeptide Modifications

by Hymonti Dey, Danijela Simonovic, Ingrid Norberg-Schulz Hagen, Terje Vasskog, Elizabeth G. Aarag Fredheim, Hans-Matti Blencke, Trude Anderssen, Morten B. Strøm and Tor Haug

Int. J. Mol. Sci. 2022, 23(22), 13844; https://doi.org/10.3390/ijms232213844 - 10 Nov 2022

Cited by 5 | Viewed by 2344

Abstract

We have synthesised short analogues of the marine antimicrobial peptide Turgencin A from the colonial Arctic ascidian Synoicum turgens. In this study, we focused on a central, cationic 12-residue Cys-Cys loop region within the sequence. Modified (tryptophan- and arginine-enriched) linear peptides were compared with Cys-Cys cyclic derivatives, and both linear and Cys-cyclic peptides were N-terminally acylated with octanoic acid (C₈), decanoic acid (C₁₀) or dodecanoic acid (C₁₂). The highest antimicrobial potency was achieved by introducing dodecanoic acid to a cyclic Turgencin A analogue with low intrinsic hydrophobicity, and by introducing octanoic acid to a cyclic analogue displaying a higher intrinsic hydrophobicity. Among all tested synthetic Turgencin A lipopeptide analogues, the most promising candidates regarding both antimicrobial and haemolytic activity were C₁₂-cTurg-1 and C₈-cTurg-2. These optimized cyclic lipopeptides displayed minimum inhibitory concentrations of 4 µg/mL against Staphylococcus aureus, Escherichia coli and the fungus Rhodothorula sp. Mode of action studies on bacteria showed a rapid membrane disruption and bactericidal effect of the cyclic lipopeptides. Haemolytic activity against human erythrocytes was low, indicating favorable selective targeting of bacterial cells. Full article

(This article belongs to the Special Issue Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition)

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20 pages, 3198 KiB

Open AccessArticle

Synthesis and Immunological Evaluation of Mannosylated Desmuramyl Dipeptides Modified by Lipophilic Triazole Substituents

by Vesna Petrović Peroković, Željka Car, Mia Bušljeta, Danijela Mihelec, Marija Paurević, Siniša Ivanković, Ranko Stojković and Rosana Ribić

Int. J. Mol. Sci. 2022, 23(15), 8628; https://doi.org/10.3390/ijms23158628 - 3 Aug 2022

Cited by 1 | Viewed by 1904

Abstract

Muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine, MDP) is the smallest peptidoglycan fragment able to trigger an immune response by activating the NOD2 receptor. Structural modification of MDP can lead to analogues with improved immunostimulating properties. The aim of this work was to prepare mannosylated desmuramyl peptides (ManDMP) containing lipophilic triazole substituents to study their immunomodulating activities in vivo. The adjuvant activity of the prepared compounds was evaluated in the mouse model using ovalbumin as an antigen and compared to the MDP and referent adjuvant ManDMPTAd. The obtained results confirm that the α-position of D-isoGln is the best position for the attachment of lipophilic substituents, especially adamantylethyl triazole. Compound 6c exhibited the strongest adjuvant activity, comparable to the MDP and better than referent ManDMPTAd. Full article

(This article belongs to the Special Issue Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition)

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32 pages, 8398 KiB

Open AccessArticle

Structural and Biofunctional Insights into the Cyclo(Pro-Pro-Phe-Phe-) Scaffold from Experimental and In Silico Studies: Melanoma and Beyond

by Joanna Bojarska, Martin Breza, Milan Remko, Malgorzata Czyz, Anna Gajos-Michniewicz, Michał Zimecki, Krzysztof Kaczmarek, Izabela D. Madura, Jakub M. Wojciechowski and Wojciech M. Wolf

Int. J. Mol. Sci. 2022, 23(13), 7173; https://doi.org/10.3390/ijms23137173 - 28 Jun 2022

Cited by 10 | Viewed by 3199

Abstract

Short peptides have great potential as safe and effective anticancer drug leads. Herein, the influence of short cyclic peptides containing the Pro-Pro-Phe-Phe sequence on patient-derived melanoma cells was investigated. Cyclic peptides such as cyclo(Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-), called CLA, and cyclo(Pro-homoPro-β³homoPhe-Phe-), called P11, exert the cytotoxic and the cytostatic effects in melanoma cells, respectively. CLA was the most active peptide as it reduced the viability of melanoma cells to 50% of control at about 10 µM, whereas P11 at about 40 µM after 48 h incubation. Interestingly, a linear derivative of P11 did not induce any effect in melanoma cells confirming previous studies showing that cyclic peptides exert better biological activity compared to their linear counterparts. According to in silico predictions, cyclic tetrapeptides show a better pharmacokinetic and toxic profile to humans than CLA. Notably, the spatial structure of those peptides containing synthetic amino acids has not been explored yet. In the Cambridge Structural Database, there is only one such cyclic tetrapeptide, cyclo((R)-β²homoPhe-D-Pro-Lys-Phe-), while in the Protein Data Bank—none. Therefore, we report the first crystal structure of cyclo(Pro-Pro-β³homoPhe-Phe-), denoted as 4B8M, a close analog of P11, which is crucial for drug discovery. Comparative molecular and supramolecular analysis of both structures was performed. The DFT findings revealed that 4B8M is well interpreted in the water solution. The results of complex Hirshfeld surface investigations on the cooperativity of interatomic contacts in terms of electrostatic and energetic features are provided. In short, the enrichment ratio revealed O^…H/H^…O and C^…H/H^…C as privileged intercontacts in the crystals in relation to basic and large supramolecular H-bonding synthon patterns. Furthermore, the ability of self-assemble 4B8M leading to a nanotubular structure is also discussed. Full article

(This article belongs to the Special Issue Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition)

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13 pages, 2325 KiB

Open AccessArticle

N-Terminal Peptide of PGLYRP1/Tag7 Is a Novel Ligand for TREM-1 Receptor

by Tatiana N. Sharapova, Olga K. Ivanova, Elena A. Romanova, Lidia P. Sashchenko and Denis V. Yashin

Int. J. Mol. Sci. 2022, 23(10), 5752; https://doi.org/10.3390/ijms23105752 - 20 May 2022

Cited by 6 | Viewed by 2399

Abstract

An investigation of innate immunity receptors sheds light on the mechanisms of inflammation and associated immune reactions. One of the key immune regulators is the TREM-1 receptor, which is involved in both inflammation and antitumor immune response. In this article, we have obtained a new ligand for the TREM-1 receptor. The peptide, named N3, is a part of the innate immune protein PGLYRP1/Tag7. It is responsible for activating the TREM-1 signaling pathway. Here, we have demonstrated that the N3 peptide acts like other TREM-1 receptor ligands: its binding results in a mild inflammation response and appearance of cytotoxic lymphocytes. We have shown that cytotoxic populations of lymphocytes in N3 peptide-treated PBMCs are similar to those treated with Tag7 or Hsp70. We also determined the part of the N3 peptide responsible for binding to TREM-1. The resulting peptide (N9) consists of nine amino acids and can be considered as a potential peptide that blocks TREM-1 signaling. Full article

(This article belongs to the Special Issue Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition)

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Review

Jump to: Editorial, Research

17 pages, 880 KiB

Open AccessReview

Therapeutic Peptides for Treatment of Lung Diseases: Infection, Fibrosis, and Cancer

by Shujiao Li, Yuying Li, Ying Liu, Yifan Wu, Qiuyu Wang, Lili Jin and Dianbao Zhang

Int. J. Mol. Sci. 2023, 24(10), 8642; https://doi.org/10.3390/ijms24108642 - 12 May 2023

Cited by 2 | Viewed by 2999

Abstract

Various lung diseases endanger people’s health. Side effects and pharmaceutical resistance complicate the treatment of acute lung injury, pulmonary fibrosis, and lung cancer, necessitating the development of novel treatments. Antimicrobial peptides (AMPs) are considered to serve as a viable alternative to conventional antibiotics. These peptides exhibit a broad antibacterial activity spectrum as well as immunomodulatory properties. Previous studies have shown that therapeutic peptides including AMPs had remarkable impacts on animal and cell models of acute lung injury, pulmonary fibrosis, and lung cancer. The purpose of this paper is to outline the potential curative effects and mechanisms of peptides in the three types of lung diseases mentioned above, which may be used as a therapeutic strategy in the future. Full article

(This article belongs to the Special Issue Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition)

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27 pages, 2244 KiB

Open AccessReview

A Comprehensive Analysis of the Intrinsic Visible Fluorescence Emitted by Peptide/Protein Amyloid-like Assemblies

by Nicole Balasco, Carlo Diaferia, Elisabetta Rosa, Alessandra Monti, Menotti Ruvo, Nunzianna Doti and Luigi Vitagliano

Int. J. Mol. Sci. 2023, 24(9), 8372; https://doi.org/10.3390/ijms24098372 - 6 May 2023

Cited by 12 | Viewed by 2718

Abstract

Amyloid aggregation is a widespread process that involves proteins and peptides with different molecular complexity and amino acid composition. The structural motif (cross-β) underlying this supramolecular organization generates aggregates endowed with special mechanical and spectroscopic properties with huge implications in biomedical and technological fields, including emerging precision medicine. The puzzling ability of these assemblies to emit intrinsic and label-free fluorescence in regions of the electromagnetic spectrum, such as visible and even infrared, usually considered to be forbidden in the polypeptide chain, has attracted interest for its many implications in both basic and applied science. Despite the interest in this phenomenon, the physical basis of its origin is still poorly understood. To gain a global view of the available information on this phenomenon, we here provide an exhaustive survey of the current literature in which original data on this fluorescence have been reported. The emitting systems have been classified in terms of their molecular complexity, amino acid composition, and physical state. Information about the wavelength of the radiation used for the excitation as well as the emission range/peak has also been retrieved. The data collected here provide a picture of the complexity of this multifaceted phenomenon that could be helpful for future studies aimed at defining its structural and electronic basis and/or stimulating new applications. Full article

(This article belongs to the Special Issue Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition)

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35 pages, 3300 KiB

Open AccessReview

Targeting Protein–Protein Interfaces with Peptides: The Contribution of Chemical Combinatorial Peptide Library Approaches

by Alessandra Monti, Luigi Vitagliano, Andrea Caporale, Menotti Ruvo and Nunzianna Doti

Int. J. Mol. Sci. 2023, 24(9), 7842; https://doi.org/10.3390/ijms24097842 - 25 Apr 2023

Cited by 7 | Viewed by 3102

Abstract

Protein–protein interfaces play fundamental roles in the molecular mechanisms underlying pathophysiological pathways and are important targets for the design of compounds of therapeutic interest. However, the identification of binding sites on protein surfaces and the development of modulators of protein–protein interactions still represent a major challenge due to their highly dynamic and extensive interfacial areas. Over the years, multiple strategies including structural, computational, and combinatorial approaches have been developed to characterize PPI and to date, several successful examples of small molecules, antibodies, peptides, and aptamers able to modulate these interfaces have been determined. Notably, peptides are a particularly useful tool for inhibiting PPIs due to their exquisite potency, specificity, and selectivity. Here, after an overview of PPIs and of the commonly used approaches to identify and characterize them, we describe and evaluate the impact of chemical peptide libraries in medicinal chemistry with a special focus on the results achieved through recent applications of this methodology. Finally, we also discuss the role that this methodology can have in the framework of the opportunities, and challenges that the application of new predictive approaches based on artificial intelligence is generating in structural biology. Full article

(This article belongs to the Special Issue Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition)

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25 pages, 10053 KiB

Open AccessReview

Transport of Biologically Active Ultrashort Peptides Using POT and LAT Carriers

by Vladimir Khavinson, Natalia Linkova, Ekaterina Kozhevnikova, Anastasiia Dyatlova and Mikhael Petukhov

Int. J. Mol. Sci. 2022, 23(14), 7733; https://doi.org/10.3390/ijms23147733 - 13 Jul 2022

Cited by 10 | Viewed by 3561

Abstract

Ultrashort peptides (USPs), consisting of 2–7 amino-acid residues, are a group of signaling molecules that regulate gene expression and protein synthesis under normal conditions in various diseases and ageing. USPs serve as a basis for the development of drugs with a targeted mechanism of action. The purpose of this review is to systematize the available data on USP transport involving POT and LAT transporters in various organs and tissues under normal, pathological and ageing conditions. The carriers of the POT family (PEPT1, PEPT2, PHT1, PHT2) transport predominantly di- and tripeptides into the cell. Methods of molecular modeling and physicochemistry have demonstrated the ability of LAT1 to transfer not only amino acids but also some di- and tripeptides into the cell and out of it. LAT1 and 2 are involved in the regulation of the antioxidant, endocrine, immune and nervous systems’ functions. Analysis of the above data allows us to conclude that, depending on their structure, di- and tripeptides can be transported into the cells of various tissues by POT and LAT transporters. This mechanism is likely to underlie the tissue specificity of peptides, their geroprotective action and effectiveness in the case of neuroimmunoendocrine system disorders. Full article

(This article belongs to the Special Issue Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition)

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15 pages, 3742 KiB

Open AccessReview

Syntheses of Polypeptides and Their Biomedical Application for Anti-Tumor Drug Delivery

by Huayang Feng, Jonas Fabrizi, Jingguo Li and Christian Mayer

Int. J. Mol. Sci. 2022, 23(9), 5042; https://doi.org/10.3390/ijms23095042 - 2 May 2022

Cited by 13 | Viewed by 3171

Abstract

Polypeptides have attracted considerable attention in recent decades due to their inherent biodegradability and biocompatibility. This mini-review focuses on various ways to synthesize polypeptides, as well as on their biomedical applications as anti-tumor drug carriers over the past five years. Various approaches to preparing polypeptides are summarized, including solid phase peptide synthesis, recombinant DNA techniques, and the polymerization of activated amino acid monomers. More details on the polymerization of specifically activated amino acid monomers, such as amino acid N-carboxyanhydrides (NCAs), amino acid N-thiocarboxyanhydrides (NTAs), and N-phenoxycarbonyl amino acids (NPCs), are introduced. Some stimuli-responsive polypeptide-based drug delivery systems that can undergo different transitions, including stability, surface, and size transition, to realize a better anti-tumor effect, are elaborated upon. Finally, the challenges and opportunities in this field are briefly discussed. Full article

(This article belongs to the Special Issue Synthetic Peptides and Peptidomimetics: From Basic Science to Biomedical Applications—2nd Edition)

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