Special Issue "Peptides of Natural Origins as Leads for Drug Discovery: From Native Structures to Peptidomimetics, Peptide-Conjugates, and Peptide-Nanoparticles"

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery".

Deadline for manuscript submissions: closed (30 April 2021).

Special Issue Editors

Prof. Dr. Luca Gentilucci
E-Mail Website
Guest Editor
1. Deoartment of Chemistry "G. Ciamician", "Alma Mater Studiorum" - University of Bologna, Bologna, Italy
2. CIRI Health Sciences and Technologies (HST), Bologna, Italy
Interests: peptides; peptidomimetics; nitrogen heterocycles; conformational analysis; docking; opioids; integrins; addiction; cancer; biomaterials; diagnostic devices; inflammation
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Dr. Fernando Albericio
E-Mail Website
Guest Editor
1. School of Chemistry, University of KwaZulu-Natal, Durban, South Africa
2. Department of Organic Chemistry, University of Barcelona, CIBER-BBN, Barcelona, Spain
Interests: antimicrobial peptides; solid-phase chemistry; combinatorial chemistry; drug delivery systems; peptide drug conjugates; orthogonal chemistry; drug discovery; biomaterials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite of recent scientific and technological advances, drug R&D productivity continues its exponential decline, dramatically depicted by the “Eroom’s Law”. This negative trend has encouraged pharmaceutical companies to reconsider bioactive natural peptides as valuable leads for drug discovery. After an initial enthusiasm until the 80s (human insulin was introduced in 1982 as the first recombinant drug), peptides almost sank into oblivion by the end of the 20th century. The reasons for this largely stem from the prejudice that the cons greatly outweigh the pros. Native peptides may suffer from poor metabolic stability, scarce to null ability to penetrate across biological barriers, and rapid clearance. Besides, inefficient and expensive manufacturing hampered the production of large amounts of peptides. Nevertheless, the past two decades have seen a significant increase in the investments in peptide drug discovery. The case of enfuvirtide demonstrated that producing a 36-residue peptide on a ton-scale per year could be cost effective. Additionally, the recourse to alternative routes of administration (e.g., pulmonary, nasal, intradermal), to the peptidomimetic strategy, and the conjugation to carriers or nanoparticles, allowed the bioavailability of native structures to be improved. Therapeutic peptides offer several advantages over small molecules—that is, greater efficacy and specificity, reduced toxicity, and reduced accumulation. Compared with proteins and antibodies, peptides have lower manufacturing costs and higher activity per unit mass, are less immunogenic, can be stored for longer periods, and have the potential to penetrate into tissues owing to their smaller size. Finally, peptides require a shorter time to reach the market, and are less problematic in terms of royalty stack because of a simpler intellectual property.

The global peptide therapeutics market was valued at USD 21.5 billion in 2016, and is expected to grow at a rate of 9.4% per year, reaching USD 48.04 billion by 2025. Presently, more than 60 peptide therapeutics are marketed worldwide, another ca. 170 are in various stages of clinical development, and more than 200 others are at preclinical stages. The predominant therapeutic areas are in metabolic diseases and oncology, followed by infections, cardiovascular, respiratory, renal, and gastro-intestinal disorders, pain, CNS, and dermatology. The year 2017 was exceptional for peptide and peptidomimetic drugs, with six approved in comparison with one in 2016: angiotensin II (control of blood pressure), etelcalcetide (secondary hyperparathyroidism), plecanatide (chronic idiopathic constipation), abaloparatide (osteoporosis), semaglutide (type 2 diabetes mellitus), and macimorelin (GH deficiency).

In this Issue, we intend to present the recent trends in peptide drug discovery, from the naturally occurring peptides to the peptidomimetics, from therapeutic applications to the new opportunities enabled by the conjugation with biomaterials and nanotechnology.

Prof. Dr. Luca Gentilucci
Prof. Dr. Fernando Albericio
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. Biomedicines 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 2000 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

  • peptide
  • peptidomimetic
  • conjugate
  • glycopeptide
  • drug discovery
  • delivery
  • cancer
  • opioid
  • metabolic
  • cardiovascular
  • antibiotic
  • synthesis
  • ligation
  • recombinant
  • GCPR
  • library
  • phage display
  • mRNA display
  • nonribosomal
  • nonstandard
  • toxin
  • lantibiotic
  • cyclotide
  • bicyclic
  • cell-penetrating

Related Special Issue

Published Papers (6 papers)

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Research

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Article
Optimization and Development of Albumin–Biopolymer Bioconjugates with Solubility-Improving Properties
Biomedicines 2021, 9(7), 737; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070737 - 26 Jun 2021
Viewed by 649
Abstract
Bioconjugation is an emerging field in the food and pharmaceutical industry. Due to its biocompatibility and high ligand binding capacity, albumin is widely used in modern drug delivery systems. However, the protein is sensitive to environmental stresses; albumin conjugates, on the other hand, [...] Read more.
Bioconjugation is an emerging field in the food and pharmaceutical industry. Due to its biocompatibility and high ligand binding capacity, albumin is widely used in modern drug delivery systems. However, the protein is sensitive to environmental stresses; albumin conjugates, on the other hand, have improved functional properties. Biopolymers are gaining interest due to their biodegradability and safety, compared to synthetic polymers. In this study, albumin–biopolymer bioconjugates were prepared by nonenzymatic Maillard reaction at 60 °C and 80% relative humidity. This nonenzymatic conjugation takes place between reducing sugars and available amino groups of a protein in certain conditions. The optimal molar ratio and time for the conjugation were studied by several investigation methods, including circular dichroism and fluorescence spectroscopy, sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE), and determination of available amino groups with ortho-phthaldialdehyde (OPA) assay. All of the measurements provided evidence for the covalent bonding of albumin and biopolymers, resulting in bioconjugates. Based on the results, a higher molar ratio and longer time are necessary to complete the reaction with the available amino groups. However, the optimal parameters are specific to each given biopolymer. The rheological behavior of the conjugates is characteristic of the initial biopolymer, which can be useful in drug development. Moreover, both the physical characteristics of albumin and the solubility-improving capacity were enhanced. Therefore, the potential use of albumin–biopolymer bioconjugates in the pharmaceutical industry could be considered. Full article
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Article
Multifunctional Enkephalin Analogs with a New Biological Profile: MOR/DOR Agonism and KOR Antagonism
Biomedicines 2021, 9(6), 625; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060625 - 31 May 2021
Viewed by 778
Abstract
In our previous studies, we developed a series of mixed MOR/DOR agonists that are enkephalin-like tetrapeptide analogs with an N-phenyl-N-piperidin-4-ylpropionamide (Ppp) moiety at the C-terminus. Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of [...] Read more.
In our previous studies, we developed a series of mixed MOR/DOR agonists that are enkephalin-like tetrapeptide analogs with an N-phenyl-N-piperidin-4-ylpropionamide (Ppp) moiety at the C-terminus. Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of LYS744 (6, Dmt-DNle-Gly-Phe(p-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPγS assay: IC50 = 52 nM, Imax = 122% cf. IC50 = 59 nM, Imax = 100% for naloxone) with nanomolar range of binding affinity (Ki = 1.3 nM cf. Ki = 2.4 nM for salvinorin A). Based on its unique biological profile, 6 is considered to possess high therapeutic potential for the treatment of chronic pain by modulating pathological KOR activation while retaining analgesic efficacy attributed to its MOR/DOR agonist activity. Full article
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Article
Physicochemical and Biological Examination of Two Glatiramer Acetate Products
Biomedicines 2019, 7(3), 49; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines7030049 - 03 Jul 2019
Cited by 2 | Viewed by 1514
Abstract
Herein we compared 40 mg/mL lots of the active ingredient, glatiramer acetate, manufactured by Mylan/Natco to the active ingredient, glatiramer acetate in Copaxone (Teva Pharmaceuticals, Ltd., Netanya Israel) using physicochemical (PCC) methods and biological assays. No differences were seen between the Mylan/Natco and [...] Read more.
Herein we compared 40 mg/mL lots of the active ingredient, glatiramer acetate, manufactured by Mylan/Natco to the active ingredient, glatiramer acetate in Copaxone (Teva Pharmaceuticals, Ltd., Netanya Israel) using physicochemical (PCC) methods and biological assays. No differences were seen between the Mylan/Natco and Teva lots with some low resolution release PCC assays (amino acid analysis, molecular weight distribution, interaction with Coomassie Brilliant Blue G-250). Changes in polydispersity between Mylan/Natco and Copaxone lots were found using size exclusion chromatography and the high resolution PCC method, known as Viscotek, and suggestive of a disparity in the homogeneity of mixture, with a shift towards high molecular weight polypeptides. Using RPLC-2D MALLS, 5 out of 8 Mylan/Natco lots fell outside the Copaxone range, containing a high molecular weight and high hydrophobicity subpopulation of polypeptides not found in Copaxone lots. Cation exchange chromatography showed differences in the surface charge distribution between the Copaxone and Mylan/Natco lots. The Mylan/Natco lots were found to be within Copaxone specifications for the EAE model, monoclonal and polyclonal binding assays and the in vitro cytotoxicity assay, however higher IL-2 secretion was shown for three Mylan/Natco lots in a potency assay. These observations provide data to inform the ongoing scientific discussion about the comparability of glatiramer acetate in Copaxone and follow-on products. Full article
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Review

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Review
Exploiting Knowledge on Structure–Activity Relationships for Designing Peptidomimetics of Endogenous Peptides
Biomedicines 2021, 9(6), 651; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060651 - 07 Jun 2021
Viewed by 714
Abstract
Endogenous peptides are important mediators in cell communication, being consequently involved in many physiological processes. Their use as therapeutic agents is limited due to their poor pharmacokinetic profile. To circumvent this drawback, alternative diverse molecules based on the stereochemical features that confer their [...] Read more.
Endogenous peptides are important mediators in cell communication, being consequently involved in many physiological processes. Their use as therapeutic agents is limited due to their poor pharmacokinetic profile. To circumvent this drawback, alternative diverse molecules based on the stereochemical features that confer their activity can be synthesized, using them as guidance; from peptide surrogates provided with a better pharmacokinetic profile, to small molecule peptidomimetics, through cyclic peptides. The design process requires a competent use of the structure-activity results available on individual peptides. Specifically, it requires synthesis and analysis of the activity of diverse analogs, biophysical information and computational work. In the present work, we show a general framework of the process and show its application to two specific examples: the design of selective AT1 antagonists of angiotensin and the design of selective B2 antagonists of bradykinin. Full article
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Review
Integrin-Targeting Peptides for the Design of Functional Cell-Responsive Biomaterials
Biomedicines 2020, 8(9), 307; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines8090307 - 25 Aug 2020
Cited by 11 | Viewed by 1523
Abstract
Integrins are a family of cell surface receptors crucial to fundamental cellular functions such as adhesion, signaling, and viability, deeply involved in a variety of diseases, including the initiation and progression of cancer, of coronary, inflammatory, or autoimmune diseases. The natural ligands of [...] Read more.
Integrins are a family of cell surface receptors crucial to fundamental cellular functions such as adhesion, signaling, and viability, deeply involved in a variety of diseases, including the initiation and progression of cancer, of coronary, inflammatory, or autoimmune diseases. The natural ligands of integrins are glycoproteins expressed on the cell surface or proteins of the extracellular matrix. For this reason, short peptides or peptidomimetic sequences that reproduce the integrin-binding motives have attracted much attention as potential drugs. When challenged in clinical trials, these peptides/peptidomimetics let to contrasting and disappointing results. In the search for alternative utilizations, the integrin peptide ligands have been conjugated onto nanoparticles, materials, or drugs and drug carrier systems, for specific recognition or delivery of drugs to cells overexpressing the targeted integrins. Recent research in peptidic integrin ligands is exploring new opportunities, in particular for the design of nanostructured, micro-fabricated, cell-responsive, stimuli-responsive, smart materials. Full article
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Review
Protein Nanotubes: From Bionanotech towards Medical Applications
Biomedicines 2019, 7(2), 46; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines7020046 - 23 Jun 2019
Cited by 5 | Viewed by 2040
Abstract
Nanobiotechnology involves the study of structures found in nature to construct nanodevices for biological and medical applications with the ultimate goal of commercialization. Within a cell most biochemical processes are driven by proteins and associated macromolecular complexes. Evolution has optimized these protein-based nanosystems [...] Read more.
Nanobiotechnology involves the study of structures found in nature to construct nanodevices for biological and medical applications with the ultimate goal of commercialization. Within a cell most biochemical processes are driven by proteins and associated macromolecular complexes. Evolution has optimized these protein-based nanosystems within living organisms over millions of years. Among these are flagellin and pilin-based systems from bacteria, viral-based capsids, and eukaryotic microtubules and amyloids. While carbon nanotubes (CNTs), and protein/peptide-CNT composites, remain one of the most researched nanosystems due to their electrical and mechanical properties, there are many concerns regarding CNT toxicity and biodegradability. Therefore, proteins have emerged as useful biotemplates for nanomaterials due to their assembly under physiologically relevant conditions and ease of manipulation via protein engineering. This review aims to highlight some of the current research employing protein nanotubes (PNTs) for the development of molecular imaging biosensors, conducting wires for microelectronics, fuel cells, and drug delivery systems. The translational potential of PNTs is highlighted. Full article
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