Special Issue in Honor of Dr. Marie-Hélène Metz-Boutigue 75th Birthday: “Recent Advances in Multifunctional Antimicrobial Peptides as Preclinical Therapeutic Studies and Clinical Future Applications”

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biologics and Biosimilars".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 25404

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Special Issue Editors


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Guest Editor
IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
Interests: antimicrobial peptides; nosocomial and cardiac infection; cardiovascular aging; cardioprotection during ischemia/reperfusion injury; cardiotoxicity of cancer chemotherapy

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Guest Editor
Institute of Biology Paris Seine FR 3631 CNRS Sorbonne University, F-75252 Paris, France
Interests: chemistry–biology interface; isolation and structural and pharmacological characterization of peptides by exploring animal biodiversity; chemical synthesis and purification of peptides; pharmacology of peptides (analgesia, antimicrobial, cancer); molecular biology

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Guest Editor
Departments of Immunology and Internal Medicine, Section of Gastroenterology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
Interests: antimicrobial peptides; autonomic nervous system; brain–gut axis; chromogranin; experimental colitis; inflammation; inflammatory bowel diseases; innate immunity; neurosciences

Special Issue Information

Dear Colleagues,

Pharmaceutics is very pleased to be hosting a Special Issue in honor of Dr. Marie-Hélène Metz-Boutigue, acknowledging her influential scientific contributions to research on Antimicrobial Peptides (AMPs).

During her career, Dr. Metz-Boutigue has published many papers in the field of the biochemical characterization of proteins and peptides, identifying new antimicrobial agents with a large spectrum against different pathogens. In the last few years, she has also studied the integration of AMPs in new functionalized antimicrobial biomaterials to prevent nosocomial infections and inflammation.

Due to her great expertise in self-endogenous AMPs belonging to the humoral immune system, she collaborated with several scientists in many publications concerning their involvement in cardiovascular diseases, inflammation, the nervous system, intestinal homeostasis and concerning the properties of these agents in immunomodulation.

This Special Issue aims to gather and highlight significant advancements for AMPs as an alternative to antibiotics for increasing resistant strains and recent discoveries for future therapeutic approaches. Since the AMPs are multifunctional peptides with antitumor and immunomodulating effects, original research articles and reviews in these fields are particularly welcome. Manuscripts regarding antimicrobial biomaterials including AMPs are also of interest.

We look forward to receiving your contributions.

Dr. Scavello Francesco
Dr. Amiche Mohamed
Prof. Dr. Jean-Eric Ghia
Guest Editors

Manuscript Submission Information

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Keywords

  • antimicrobial peptides
  • antimicrobial biomaterials
  • multifunctional antimicrobial peptides
  • antitumor peptides
  • immunomodulation
  • inflammation

Published Papers (14 papers)

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Editorial

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6 pages, 224 KiB  
Editorial
The Editorial Position on ‘Recent Advances in Multifunctional Antimicrobial Peptides as Preclinical Therapeutic Studies and Clinical Future Applications’
by Francesco Scavello, Mohamed Amiche and Jean-Eric Ghia
Pharmaceutics 2023, 15(10), 2383; https://doi.org/10.3390/pharmaceutics15102383 - 26 Sep 2023
Viewed by 764
Abstract
Antibiotic resistance has recently been recognized as an alarming issue and one of the leading causes of death worldwide [...] Full article

Research

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12 pages, 4759 KiB  
Article
Impacts of PEGylation and Glycosylation on the Biological Properties of Host Defense Peptide IDR1018
by Hashem Etayash, Fione Yip and Robert E. W. Hancock
Pharmaceutics 2023, 15(5), 1391; https://doi.org/10.3390/pharmaceutics15051391 - 1 May 2023
Cited by 1 | Viewed by 1364
Abstract
The multifunctional properties of host defense peptides (HDPs) make them promising drug candidates to tackle bacterial infections and tissue inflammation. However, these peptides tend to aggregate and can harm host cells at high doses, potentially limiting their clinical use and applications. In this [...] Read more.
The multifunctional properties of host defense peptides (HDPs) make them promising drug candidates to tackle bacterial infections and tissue inflammation. However, these peptides tend to aggregate and can harm host cells at high doses, potentially limiting their clinical use and applications. In this study, we explored the influences of both pegylation and glycosylation on the biocompatibility and biological properties of HDPs, particularly the innate defense regulator IDR1018. Two peptide conjugates were designed by attaching either polyethylene glycol (PEG6) or a glucose moiety to the peptide towards the N-terminus. Significantly, both derivatives reduced the aggregation, hemolysis, and cytotoxicity of the parent peptide by orders of magnitude. In addition, while the pegylated conjugate, PEG6-IDR1018, retained an excellent immunomodulatory profile, similar to that observed for IDR1018 itself, the glycosylated conjugate, Glc-IDR1018, significantly outperformed the parent peptide in inducing anti-inflammatory mediators, MCP1 and IL-1RA and in suppressing the level of lipopolysaccharide-induced proinflammatory cytokine IL-1β. Conversely, the conjugates led to a partial reduction in antimicrobial and antibiofilm activity. These findings underline the impacts of both pegylation and glycosylation on the biological properties of the HDP IDR1018 and indicate the potential of glycosylation to enhance the design of highly effective immunomodulatory peptides. Full article
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21 pages, 2687 KiB  
Article
Determination of Mutational Timing of Colistin-Resistance Genes through Klebsiella pneumoniae Evolution
by Jenna M. Kuhn and Yuanpu Peter Di
Pharmaceutics 2023, 15(1), 270; https://doi.org/10.3390/pharmaceutics15010270 - 12 Jan 2023
Cited by 6 | Viewed by 2007
Abstract
The emergence and dissemination of carbapenem-resistant Klebsiella pneumoniae (KP), one of the carbapenem-resistant Enterobacteriaceae (CRE), is now an emerging cause of antibiotic-resistant nosocomial infections associated with high rates of morbidity and mortality. Colistin, or polymyxin E, is a last-resort peptide antibiotic used to [...] Read more.
The emergence and dissemination of carbapenem-resistant Klebsiella pneumoniae (KP), one of the carbapenem-resistant Enterobacteriaceae (CRE), is now an emerging cause of antibiotic-resistant nosocomial infections associated with high rates of morbidity and mortality. Colistin, or polymyxin E, is a last-resort peptide antibiotic used to treat multidrug-resistant (MDR) Gram-negative bacterial infections including KP. Unfortunately, resistance to colistin is rising with increasing use in the clinical setting. Although clinical evidence links certain mutations to colistin resistance (COL-R) in KP, the origination and association of the mutations remain unclear. We hypothesize that the timing of COL-R mutations influences the development and progression of KP resistance to colistin. We performed planktonic and biofilm in vitro experimental evolutions of KP strain ATCC 43816 under increasing colistin concentrations to characterize the temporal regulation of critical COL-R mutations throughout COL-R progression. The resistance generation and mutation profiles of independently evolved bacterial populations with different lifestyles were compared. Genes with various functions theorize the timeline in which key mutations are generated and their roles in the progression of COL-R. Our results aim to advance the research and development of effective therapeutics to treat MDR bacterial infection as the dissemination of CRE continues to be a severe public health threat. Full article
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10 pages, 280 KiB  
Article
In Vivo Evaluation of the Efficacy of a Nisin–Biogel as a New Approach for Canine Periodontal Disease Control
by Eva Cunha, Luís Miguel Carreira, Telmo Nunes, Marta Videira, Luís Tavares, Ana Salomé Veiga and Manuela Oliveira
Pharmaceutics 2022, 14(12), 2716; https://doi.org/10.3390/pharmaceutics14122716 - 4 Dec 2022
Cited by 2 | Viewed by 1776
Abstract
Periodontal disease (PD) is a common oral disease in dogs. Recent in vitro research revealed that nisin–biogel is a promising compound for canine PD control. In this work, a clinical trial was developed to assess the in vivo efficacy of nisin–biogel in dogs [...] Read more.
Periodontal disease (PD) is a common oral disease in dogs. Recent in vitro research revealed that nisin–biogel is a promising compound for canine PD control. In this work, a clinical trial was developed to assess the in vivo efficacy of nisin–biogel in dogs by determining the dental plaque index (DPI), gingivitis index (GI), and periodontal pocket depth (PPD) after dental administration. The biogel’s influence on aerobic bacteria counts was also evaluated, as well as its acceptance/adverse effects in dogs. Twenty animals were allocated to one of two groups: a treatment group (TG) subjected to a dental topical application of nisin–biogel for 90 days and a control group (CG) with no treatment. Besides daily monitoring, on day 1 (T0) and at the end of the assay (T90), animals were subjected to blood analysis, periodontal evaluation, dental plaque sampling, scaling, and polishing. Statistical analysis with mixed models showed a significant reduction in mean PPD (estimate = −0.371, p-value < 0.001) and DPI (estimate = −0.146, p-value < 0.05) in the TG animals at T90. A reduction in the GI (estimate = −0.056, p-value > 0.05) was also observed but with no statistical significance. No influence on total bacterial counts was observed, and no adverse effects were detected. The nisin–biogel was revealed to be a promising compound for canine PD control. Full article
14 pages, 2743 KiB  
Article
Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics
by Michel Siegel, Guido Steiner, Linnea C. Franssen, Francesca Carratu, James Herron, Katharina Hartman, Cary M. Looney, Axel Ducret, Katharine Bray-French, Olivier Rohr, Timothy P. Hickling, Noel Smith and Céline Marban-Doran
Pharmaceutics 2022, 14(12), 2672; https://doi.org/10.3390/pharmaceutics14122672 - 1 Dec 2022
Cited by 9 | Viewed by 2967
Abstract
Immunogenicity, defined as the ability to provoke an immune response, can be either wanted (i.e., vaccines) or unwanted. The latter refers to an immune response to protein or peptide therapeutics, characterized by the production of anti-drug antibodies, which may affect the efficacy and/or [...] Read more.
Immunogenicity, defined as the ability to provoke an immune response, can be either wanted (i.e., vaccines) or unwanted. The latter refers to an immune response to protein or peptide therapeutics, characterized by the production of anti-drug antibodies, which may affect the efficacy and/or the safety profiles of these drugs. Consequently, evaluation of the risk of immunogenicity early in the development of biotherapeutics is of critical importance for defining their efficacy and safety profiles. Here, we describe and validate a fit-for-purpose FluoroSpot-based in vitro assay for the evaluation of drug-specific T cell responses. A panel of 24 biotherapeutics with a wide range of clinical anti-drug antibody response rates were tested in this assay. We demonstrated that using suitable cutoffs and donor cohort sizes, this assay could identify most of the compounds with high clinical immunogenicity rates (71% and 78% for sensitivity and specificity, respectively) while we characterized the main sources of assay variability. Overall, these data indicate that the dendritic cell and CD4+ T cell restimulation assay published herein could be a valuable tool to assess the risk of drug-specific T cell responses and contribute to the selection of clinical candidates in early development. Full article
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15 pages, 6259 KiB  
Article
Pulmonary Safety Profile of Esc Peptides and Esc-Peptide-Loaded Poly(lactide-co-glycolide) Nanoparticles: A Promising Therapeutic Approach for Local Treatment of Lung Infectious Diseases
by Floriana Cappiello, Bruno Casciaro, Maria Rosa Loffredo, Elena Puglisi, Qiao Lin, Dandan Yang, Gemma Conte, Ivana d’Angelo, Francesca Ungaro, Loretta Ferrera, Raffaella Barbieri, Laura Cresti, Alessandro Pini, Yuanpu Peter Di and Maria Luisa Mangoni
Pharmaceutics 2022, 14(11), 2297; https://doi.org/10.3390/pharmaceutics14112297 - 26 Oct 2022
Cited by 5 | Viewed by 1405
Abstract
In recent years, we have discovered Esc(1-21) and its diastereomer (Esc peptides) as valuable candidates for the treatment of Pseudomonas lung infection, especially in patients with cystic fibrosis (CF). Furthermore, engineered poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) were revealed to be a promising pulmonary delivery [...] Read more.
In recent years, we have discovered Esc(1-21) and its diastereomer (Esc peptides) as valuable candidates for the treatment of Pseudomonas lung infection, especially in patients with cystic fibrosis (CF). Furthermore, engineered poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) were revealed to be a promising pulmonary delivery system of antimicrobial peptides. However, the “ad hoc” development of novel therapeutics requires consideration of their stability, tolerability, and safety. Hence, by means of electrophysiology experiments and preclinical studies on healthy mice, we demonstrated that neither Esc peptides or Esc-peptide-loaded PLGA NPs significantly affect the integrity of the lung epithelium, nor change the global gene expression profile of lungs of treated animals compared to those of vehicle-treated animals. Noteworthy, the Esc diastereomer endowed with the highest antimicrobial activity did not provoke any pulmonary pro-inflammatory response, even at a concentration 15-fold higher than the efficacy dosage 24 h after administration in the free or encapsulated form. The therapeutic index was ≥70, and the peptide was found to remain available in the bronchoalveolar lavage of mice, after two days of incubation. Overall, these studies should open an avenue for a new up-and-coming pharmacological approach, likely based on inhalable peptide-loaded NPs, to address CF lung disease. Full article
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16 pages, 2466 KiB  
Article
Antimicrobial Peptides and Biomarkers Induced by Ultraviolet Irradiation Have the Potential to Reduce Endodontic Inflammation and Facilitate Tissue Healing
by Kimberly A. Morio, Robert H. Sternowski, Erliang Zeng and Kim A. Brogden
Pharmaceutics 2022, 14(9), 1979; https://doi.org/10.3390/pharmaceutics14091979 - 19 Sep 2022
Cited by 3 | Viewed by 1574
Abstract
Background: Ultraviolet (UV) irradiation can modulate host immune responses and this approach is a novel application for treating endodontic infections and inflammation in root canals. Methods: A dataset of UV-induced molecules was compiled from a literature search. A subset of this dataset was [...] Read more.
Background: Ultraviolet (UV) irradiation can modulate host immune responses and this approach is a novel application for treating endodontic infections and inflammation in root canals. Methods: A dataset of UV-induced molecules was compiled from a literature search. A subset of this dataset was used to calculate expression log2 ratios of endodontic tissue molecules from HEPM cells and gingival fibroblasts after 255, 405, and 255/405 nm UV irradiation. Both datasets were analyzed using ingenuity pathway analysis (IPA, Qiagen, Germantown, MD, USA). Statistical significance was calculated using Fisher’s exact test and z-scores were calculated for IPA comparison analysis. Results: The dataset of 32 UV-induced molecules contained 9 antimicrobial peptides, 10 cytokines, 6 growth factors, 3 enzymes, 2 transmembrane receptors, and 2 transcription regulators. These molecules were in the IPA canonical pathway annotations for the wound healing signaling pathway (9/32, p = 3.22 × 10−11) and communication between immune cells (6/32, p = 8.74 × 10−11). In the IPA disease and function annotations, the 32 molecules were associated with an antimicrobial response, cell-to-cell signaling and interaction, cellular movement, hematological system development and function, immune cell trafficking, and inflammatory response. In IPA comparison analysis of the 13 molecules, the predicted activation or inhibition of pathways depended upon the cell type exposed, the wavelength of the UV irradiation used, and the time after exposure. Conclusions: UV irradiation activates and inhibits cellular pathways and immune functions. These results suggested that UV irradiation can activate innate and adaptive immune responses, which may supplement endodontic procedures to reduce infection, inflammation, and pain and assist tissues to heal. Full article
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15 pages, 2089 KiB  
Article
Structure of Lacticaseicin 30 and Its Engineered Variants Revealed an Interplay between the N-Terminal and C-Terminal Regions in the Activity against Gram-Negative Bacteria
by Désiré Madi-Moussa, Barbara Deracinois, Radja Teiar, Yanyan Li, Marius Mihasan, Christophe Flahaut, Sylvie Rebuffat, Françoise Coucheney and Djamel Drider
Pharmaceutics 2022, 14(9), 1921; https://doi.org/10.3390/pharmaceutics14091921 - 12 Sep 2022
Cited by 2 | Viewed by 1702
Abstract
Lacticaseicin 30 is one of the five bacteriocins produced by the Gram-positive Lacticaseibacillus paracasei CNCM I-5369. This 111 amino acid bacteriocin is noteworthy for being active against Gram-negative bacilli including Escherichia coli strains resistant to colistin. Prediction of the lacticaseicin 30 structure using [...] Read more.
Lacticaseicin 30 is one of the five bacteriocins produced by the Gram-positive Lacticaseibacillus paracasei CNCM I-5369. This 111 amino acid bacteriocin is noteworthy for being active against Gram-negative bacilli including Escherichia coli strains resistant to colistin. Prediction of the lacticaseicin 30 structure using the Alphafold2 pipeline revealed a largely helical structure including five helix segments, which was confirmed by circular dichroism. To identify the structural requirements of the lacticaseicin 30 activity directed against Gram-negative bacilli, a series of variants, either shortened or containing point mutations, was heterologously produced in Escherichia coli and assayed for their antibacterial activity against a panel of target strains including Gram-negative bacteria and the Gram-positive Listeria innocua. Lacticaseicin 30 variants comprising either the N-terminal region (amino acids 1 to 39) or the central and C-terminal regions (amino acids 40 to 111) were prepared. Furthermore, mutations were introduced by site-directed mutagenesis to obtain ten bacteriocin variants E6G, T7P, E32G, T33P, T52P, D57G, A74P, Y78S, Y93S and A97P. Compared to lacticaseicin 30, the anti-Gram-negative activity of the N-terminal peptide and variants E32G, T33P and D57G remained almost unchanged, while that of the C-terminal peptide and variants E6G, T7P, T52P, A74P, Y78S, Y93S and A97P was significantly altered. Finally, the N-terminal region was further shortened to keep only the first 20 amino acid part that was predicted to include the first helix. The anti-Gram-negative activity of this truncated peptide was completely abolished. Overall, this study shows that activity of lacticaseicin 30, one of the rare Gram-positive bacteriocins inhibiting Gram-negative bacteria, requires at least two helices in the N-terminal region and that the C-terminal region carries amino acids playing a role in modulation of the activity. Taken together, these data will help to design forthcoming variants of lacticaseicin 30 as promising therapeutic agents to treat infections caused by Gram-negative bacilli. Full article
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Review

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19 pages, 4569 KiB  
Review
Catestatin: Antimicrobial Functions and Potential Therapeutics
by Suborno Jati, Sumana Mahata, Soumita Das, Saurabh Chatterjee and Sushil K. Mahata
Pharmaceutics 2023, 15(5), 1550; https://doi.org/10.3390/pharmaceutics15051550 - 20 May 2023
Cited by 4 | Viewed by 1378
Abstract
The rapid increase in drug-resistant and multidrug-resistant infections poses a serious challenge to antimicrobial therapies, and has created a global health crisis. Since antimicrobial peptides (AMPs) have escaped bacterial resistance throughout evolution, AMPs are a category of potential alternatives for antibiotic-resistant “superbugs”. The [...] Read more.
The rapid increase in drug-resistant and multidrug-resistant infections poses a serious challenge to antimicrobial therapies, and has created a global health crisis. Since antimicrobial peptides (AMPs) have escaped bacterial resistance throughout evolution, AMPs are a category of potential alternatives for antibiotic-resistant “superbugs”. The Chromogranin A (CgA)-derived peptide Catestatin (CST: hCgA352–372; bCgA344–364) was initially identified in 1997 as an acute nicotinic-cholinergic antagonist. Subsequently, CST was established as a pleiotropic hormone. In 2005, it was reported that N-terminal 15 amino acids of bovine CST (bCST1–15 aka cateslytin) exert antibacterial, antifungal, and antiyeast effects without showing any hemolytic effects. In 2017, D-bCST1–15 (where L-amino acids were changed to D-amino acids) was shown to exert very effective antimicrobial effects against various bacterial strains. Beyond antimicrobial effects, D-bCST1–15 potentiated (additive/synergistic) antibacterial effects of cefotaxime, amoxicillin, and methicillin. Furthermore, D-bCST1–15 neither triggered bacterial resistance nor elicited cytokine release. The present review will highlight the antimicrobial effects of CST, bCST1–15 (aka cateslytin), D-bCST1–15, and human variants of CST (Gly364Ser-CST and Pro370Leu-CST); evolutionary conservation of CST in mammals; and their potential as a therapy for antibiotic-resistant “superbugs”. Full article
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15 pages, 1349 KiB  
Review
Antimicrobial Proteins: Structure, Molecular Action, and Therapeutic Potential
by Mohamed Hassan, Thomas W. Flanagan, Naji Kharouf, Christelle Bertsch, Davide Mancino and Youssef Haikel
Pharmaceutics 2023, 15(1), 72; https://doi.org/10.3390/pharmaceutics15010072 - 26 Dec 2022
Cited by 12 | Viewed by 2643
Abstract
Second- and third-line treatments of patients with antibiotic-resistant infections can have serious side effects, such as organ failure with prolonged care and recovery. As clinical practices such as cancer therapies, chronic disease treatment, and organ transplantation rely on the ability of available antibiotics [...] Read more.
Second- and third-line treatments of patients with antibiotic-resistant infections can have serious side effects, such as organ failure with prolonged care and recovery. As clinical practices such as cancer therapies, chronic disease treatment, and organ transplantation rely on the ability of available antibiotics to fight infection, the increased resistance of microbial pathogens presents a multifaceted, serious public health concern worldwide. The pipeline of traditional antibiotics is exhausted and unable to overcome the continuously developing multi-drug resistance. To that end, the widely observed limitation of clinically utilized antibiotics has prompted researchers to find a clinically relevant alternate antimicrobial strategy. In recent decades, the discovery of antimicrobial peptides (AMPs) as an excellent candidate to overcome antibiotic resistance has received further attention, particularly from scientists, health professionals, and the pharmaceutical industry. Effective AMPs are characterized by a broad spectrum of antimicrobial activities, high pathogen specificity, and low toxicity. In addition to their antimicrobial activity, AMPs have been found to be involved in a variety of biological functions, including immune regulation, angiogenesis, wound healing, and antitumor activity. This review provides a current overview of the structure, molecular action, and therapeutic potential of AMPs. Full article
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18 pages, 341 KiB  
Review
Our Experience over 20 Years: Antimicrobial Peptides against Gram Positives, Gram Negatives, and Fungi
by Giulio Rizzetto, Daisy Gambini, Andrea Maurizi, Matteo Candelora, Elisa Molinelli, Oscar Cirioni, Lucia Brescini, Andrea Giacometti, Annamaria Offidani and Oriana Simonetti
Pharmaceutics 2023, 15(1), 40; https://doi.org/10.3390/pharmaceutics15010040 - 22 Dec 2022
Cited by 10 | Viewed by 1253
Abstract
Antibiotic resistance is rapidly increasing, and new anti-infective therapies are urgently needed. In this regard, antimicrobial peptides (AMPs) may represent potential candidates for the treatment of infections caused by multiresistant microorganisms. In this narrative review, we reported the experience of our research group [...] Read more.
Antibiotic resistance is rapidly increasing, and new anti-infective therapies are urgently needed. In this regard, antimicrobial peptides (AMPs) may represent potential candidates for the treatment of infections caused by multiresistant microorganisms. In this narrative review, we reported the experience of our research group over 20 years. We described the AMPs we evaluated against Gram-positive, Gram-negative, and fungi. In conclusion, our experience shows that AMPs can be a key option for treating multiresistant infections and overcoming resistance mechanisms. The combination of AMPs allows antibiotics and antifungals that are no longer effective to exploit the synergistic effect by restoring their efficacy. A current limitation includes poor data on human patients, the cost of some AMPs, and their safety, which is why studies on humans are needed as soon as possible. Full article
14 pages, 987 KiB  
Review
Neuropilin-1 and Integrins as Receptors for Chromogranin A-Derived Peptides
by Angelo Corti, Giulia Anderluzzi and Flavio Curnis
Pharmaceutics 2022, 14(12), 2555; https://doi.org/10.3390/pharmaceutics14122555 - 22 Nov 2022
Cited by 3 | Viewed by 1804
Abstract
Human chromogranin A (CgA), a 439 residue-long member of the “granin” secretory protein family, is the precursor of several peptides and polypeptides involved in the regulation of the innate immunity, cardiovascular system, metabolism, angiogenesis, tissue repair, and tumor growth. Despite the [...] Read more.
Human chromogranin A (CgA), a 439 residue-long member of the “granin” secretory protein family, is the precursor of several peptides and polypeptides involved in the regulation of the innate immunity, cardiovascular system, metabolism, angiogenesis, tissue repair, and tumor growth. Despite the many biological activities observed in experimental and preclinical models for CgA and its most investigated fragments (vasostatin-I and catestatin), limited information is available on the receptor mechanisms underlying these effects. The interaction of vasostatin-1 with membrane phospholipids and the binding of catestatin to nicotinic and b2-adrenergic receptors have been proposed as important mechanisms for some of their effects on the cardiovascular and sympathoadrenal systems. Recent studies have shown that neuropilin-1 and certain integrins may also work as high-affinity receptors for CgA, vasostatin-1 and other fragments. In this case, we review the results of these studies and discuss the structural requirements for the interactions of CgA-related peptides with neuropilin-1 and integrins, their biological effects, their mechanisms, and the potential exploitation of compounds that target these ligand-receptor systems for cancer diagnosis and therapy. The results obtained so far suggest that integrins (particularly the integrin avb6) and neuropilin-1 are important receptors that mediate relevant pathophysiological functions of CgA and CgA fragments in angiogenesis, wound healing, and tumor growth, and that these interactions may represent important targets for cancer imaging and therapy. Full article
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12 pages, 1323 KiB  
Review
Chromogranin A and Its Fragments in the Critically Ill: An Expanding Domain of Interest for Better Care
by Francis Schneider, Raphaël Clère-Jehl, Francesco Scavello, Thierry Lavigne, Angelo Corti, Tommaso Angelone, Youssef Haïkel and Philippe Lavalle
Pharmaceutics 2022, 14(10), 2178; https://doi.org/10.3390/pharmaceutics14102178 - 12 Oct 2022
Cited by 1 | Viewed by 1355
Abstract
Life-threatening diseases challenge immunity with a release of chromogranins. This report focuses on Chromogranin A (CGA) and some of its derived peptides in critically ill patients, with attention paid to their potential to become biomarkers of severity and actors of defense. First, we [...] Read more.
Life-threatening diseases challenge immunity with a release of chromogranins. This report focuses on Chromogranin A (CGA) and some of its derived peptides in critically ill patients, with attention paid to their potential to become biomarkers of severity and actors of defense. First, we studied whether circulating CGA may be a biomarker of outcome in non-selected critically ill patients: CGA concentrations were reliably associated with short-term death, systemic inflammation, and multiple organ failure. Additionally, when studying Vasostatin-I, the major N-terminal fragment of CGA, we noted its reliable prognostic value as early as admission if associated with age and lactate. In trauma patients, CGA concentrations heralded the occurrence of care-related infections. This was associated with an in vitro inhibitor impact of Chromofungin on both NF-kappa B- and API-transcriptional activities. Secondly, in life-threatening disease-induced oxidative stress, the multimerization of Vasostatin-I occurs with the loss of its anti-microbial properties ex vivo. In vivo, a 4%-concentration of non-oxidized albumin infusion reversed multimerization with a decrease in care-related infections. Finally, in vitro Catestatin impacted the polymorphonuclear cells-Ca++-dependent, calmodulin–regulated iPLA2 pathway by releasing immunity-related proteins. Furthermore, human Cateslytin, the active domain of Catestatin, helped destroy S. aureus: this prompted the creation of synthetic D-stereoisomer of CGA-derived peptides against superbugs for the protection of implanted devices. In conclusion, CGA consideration in the critically ill is only starting, but it offers interesting perspectives for improved outcomes. Full article
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14 pages, 1228 KiB  
Review
Recent Advances in Multifunctional Antimicrobial Peptides as Immunomodulatory and Anticancer Therapy: Chromogranin A-Derived Peptides and Dermaseptins as Endogenous versus Exogenous Actors
by Francesco Scavello, Mohamed Amiche and Jean-Eric Ghia
Pharmaceutics 2022, 14(10), 2014; https://doi.org/10.3390/pharmaceutics14102014 - 22 Sep 2022
Cited by 5 | Viewed by 1612
Abstract
Antimicrobial peptides (AMPs) are produced by all living organisms exhibiting antimicrobial activities and representing the first line of innate defense against pathogens. In this context, AMPs are suggested as an alternative to classical antibiotics. However, several researchers reported their involvement in different processes [...] Read more.
Antimicrobial peptides (AMPs) are produced by all living organisms exhibiting antimicrobial activities and representing the first line of innate defense against pathogens. In this context, AMPs are suggested as an alternative to classical antibiotics. However, several researchers reported their involvement in different processes defining them as Multifunctional AMPs (MF-AMPs). Interestingly, these agents act as the endogenous responses of the human organism against several dangerous stimuli. Still, they are identified in other organisms and evaluated for their anticancer therapy. Chromogranin A (CgA) is a glyco-phosphoprotein discovered for the first time in the adrenal medulla but also produced in several cells. CgA can generate different derived AMPs influencing numerous physiological processes. Dermaseptins (DRSs) are a family of α-helical-shaped polycationic peptides isolated from the skin secretions of several leaf frogs from the Phyllomedusidae family. Several DRSs were identified as AMPs and, until now, more than 65 DRSs have been classified. Recently, these exogenous molecules were characterized for their anticancer activity. In this review, we summarize the role of these two classes of MF-AMPs as an example of endogenous molecules for CgA-derived peptides, able to modulate inflammation but also as exogenous molecules for DRSs, exerting anticancer activities. Full article
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