Peptides of Natural Origin as Leads for Drug Discovery: From Native Structures to Peptidomimetics, Peptide-Conjugates, and Peptide-Nanoparticles 2.0

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

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 17146

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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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Special Issue Information

Dear Colleagues,

Despite recent scientific and technological advances, drug R&D productivity continues to exponentially decline, dramatically depicted by “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 1980s (human insulin was introduced in 1982 as the first recombinant drug), peptides had almost sunk 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 biological barriers, and rapid clearance. Besides, inefficient and expensive manufacturing have hampered the production of large amounts of peptides. Nevertheless, the past two decades have seen a significant increase in investment 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, and intradermal) and to the peptidomimetic strategy, and 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 less time to reach the market and are less problematic in terms of royalty stacking because of the 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. More than 60 peptide therapeutics are currently 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 gastrointestinal disorders; pain; the CNS; and dermatology. The year 2017 was exceptional for peptide and peptidomimetic drugs, with six approved, in comparison with one in 2016: angiotensin II (for the control of blood pressure), etelcalcetide (for secondary hyperparathyroidism), plecanatide (for chronic idiopathic constipation), abaloparatide (for osteoporosis), semaglutide (for type 2 diabetes mellitus), and macimorelin (for GH deficiency).

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

Prof. Dr. Luca Gentilucci
Guest Editor

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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

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Published Papers (7 papers)

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Research

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22 pages, 4116 KiB  
Article
A Conjugate between Lqh-8/6, a Natural Peptide Analogue of Chlorotoxin, and Doxorubicin Efficiently Induces Glioma Cell Death
by Lucie Dardevet, Feten Najlaoui, Sonia Aroui, Mayeul Collot, Céline Tisseyre, Michael W. Pennington, Jean-Maurice Mallet and Michel De Waard
Biomedicines 2022, 10(10), 2605; https://doi.org/10.3390/biomedicines10102605 - 17 Oct 2022
Cited by 2 | Viewed by 1697
Abstract
Natural peptides isolated from animal venoms generally target cell surface receptors with high affinity and selectivity. On many occasions, some of these receptors are over-expressed in cancer cells. Herein, we identified Lqh-8/6 as a natural peptide analog of chlorotoxin, a proven and useful [...] Read more.
Natural peptides isolated from animal venoms generally target cell surface receptors with high affinity and selectivity. On many occasions, some of these receptors are over-expressed in cancer cells. Herein, we identified Lqh-8/6 as a natural peptide analog of chlorotoxin, a proven and useful compound for the diagnosis and treatment of glioma. Lqh-8/6 and two other natural analogues were chemically synthesized for the first time and evaluated for their ability to label, detect and prevent glioma growth in vitro. We demonstrate that a biotinylated version of Lqh-8/6 allows both the labeling of glioma cell lines and the detection of glioma in brain sections of glioma allograft Fisher rats. Lqh-8/6 has intrinsic anti-invasive properties but is non-toxic to glioma cells. To confer anti-tumor properties to Lqh-8/6, we chemically coupled doxorubicin to the glioma-targeting peptide using click chemistry. To this end, we successfully chemically synthesized Lqh-8/6-azide and doxorubicin-alkyne without impairing the toxic nature of doxorubicin. The toxin-drug conjugate efficiently promotes the apoptosis of glioma cells in vitro. This example contributes to the concept that animal venom peptides constitute exquisite warheads for delivering toxic chemical conjugates, a parallel to the popular concept of antibody-drug conjugates for the treatment of cancer. Full article
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13 pages, 8804 KiB  
Article
Examining Topoisomers of a Snake-Venom-Derived Peptide for Improved Antimicrobial and Antitumoral Properties
by Adam Carrera-Aubesart, Sira Defaus, Clara Pérez-Peinado, Daniel Sandín, Marc Torrent, Maria Ángeles Jiménez and David Andreu
Biomedicines 2022, 10(9), 2110; https://doi.org/10.3390/biomedicines10092110 - 29 Aug 2022
Cited by 4 | Viewed by 1530
Abstract
Ctn[15-34], the C-terminal section of crotalicidin (Ctn), a cathelicidin from a South American pit viper, is an antimicrobial and antitumoral peptide with remarkably longer stability in human serum than the parent Ctn. In this work, a set of topoisomers of both Ctn and [...] Read more.
Ctn[15-34], the C-terminal section of crotalicidin (Ctn), a cathelicidin from a South American pit viper, is an antimicrobial and antitumoral peptide with remarkably longer stability in human serum than the parent Ctn. In this work, a set of topoisomers of both Ctn and Ctn[15-34], including the retro, enantio, and retroenantio versions, were synthesized and tested to investigate the structural requirements for activity. All topoisomers were as active as the cognate sequences against Gram-negative bacteria and tumor cells while slightly more toxic towards normal cells. More importantly, the enhanced serum stability of the D-amino-acid-containing versions suggests that such topoisomers must be preferentially considered as future antimicrobial and anticancer peptide leads. Full article
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17 pages, 3524 KiB  
Article
The Tarantula Toxin ω-Avsp1a Specifically Inhibits Human CaV3.1 and CaV3.3 via the Extracellular S3-S4 Loop of the Domain 1 Voltage-Sensor
by Volker Herzig, Yong-Cyuan Chen, Yanni K.-Y. Chin, Zoltan Dekan, Yu-Wang Chang, Hui-Ming Yu, Paul F. Alewood, Chien-Chang Chen and Glenn F. King
Biomedicines 2022, 10(5), 1066; https://doi.org/10.3390/biomedicines10051066 - 04 May 2022
Cited by 3 | Viewed by 2085
Abstract
Inhibition of T-type calcium channels (CaV3) prevents development of diseases related to cardiovascular and nerve systems. Further, knockout animal studies have revealed that some diseases are mediated by specific subtypes of CaV3. However, subtype-specific CaV3 inhibitors for [...] Read more.
Inhibition of T-type calcium channels (CaV3) prevents development of diseases related to cardiovascular and nerve systems. Further, knockout animal studies have revealed that some diseases are mediated by specific subtypes of CaV3. However, subtype-specific CaV3 inhibitors for therapeutic purposes or for studying the physiological roles of CaV3 subtypes are missing. To bridge this gap, we employed our spider venom library and uncovered that Avicularia spec. (“Amazonas Purple”, Peru) tarantula venom inhibited specific T-type CaV channel subtypes. By using chromatographic and mass-spectrometric techniques, we isolated and sequenced the active toxin ω-Avsp1a, a C-terminally amidated 36 residue peptide with a molecular weight of 4224.91 Da, which comprised the major peak in the venom. Both native (4.1 μM) and synthetic ω-Avsp1a (10 μM) inhibited 90% of CaV3.1 and CaV3.3, but only 25% of CaV3.2 currents. In order to investigate the toxin binding site, we generated a range of chimeric channels from the less sensitive CaV3.2 and more sensitive CaV3.3. Our results suggest that domain-1 of CaV3.3 is important for the inhibitory effect of ω-Avsp1a on T-type calcium channels. Further studies revealed that a leucine of T-type calcium channels is crucial for the inhibitory effect of ω-Avsp1a. Full article
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21 pages, 4840 KiB  
Article
Design of α/β-Hybrid Peptide Ligands of α4β1 Integrin Equipped with a Linkable Side Chain for Chemoselective Biofunctionalization of Microstructured Materials
by Michele Anselmi, Monica Baiula, Federica Santino, Junwei Zhao, Santi Spampinato, Natalia Calonghi and Luca Gentilucci
Biomedicines 2021, 9(11), 1737; https://doi.org/10.3390/biomedicines9111737 - 21 Nov 2021
Cited by 5 | Viewed by 1915
Abstract
Arg-Gly-Asp (RGD)-binding integrins, e.g., αvβ3, αvβ1, αvβ5 integrins, are currently regarded as privileged targets for the delivery of diagnostic and theranostic agents, especially in cancer treatment. In contrast, scarce attention has been paid so far to the diagnostic opportunities promised by integrins that [...] Read more.
Arg-Gly-Asp (RGD)-binding integrins, e.g., αvβ3, αvβ1, αvβ5 integrins, are currently regarded as privileged targets for the delivery of diagnostic and theranostic agents, especially in cancer treatment. In contrast, scarce attention has been paid so far to the diagnostic opportunities promised by integrins that recognize other peptide motifs. In particular, α4β1 integrin is involved in inflammatory, allergic, and autoimmune diseases, therefore, it represents an interesting therapeutic target. Aiming at obtaining simple, highly stable ligands of α4β1 integrin, we designed hybrid α/β peptidomimetics carrying linkable side chains for the expedient functionalization of biomaterials, nano- and microparticles. We identified the prototypic ligands MPUPA-(R)-isoAsp(NHPr)-Gly-OH (12) and MPUPA-Dap(Ac)-Gly-OH (13) (MPUPA, methylphenylureaphenylacetic acid; Dap, 2,3-diamino propionic acid). Modification of 12 and 13 by introduction of flexible linkers at isoAsp or Dap gave 49 and 50, respectively, which allowed for coating with monolayers (ML) of flat zeolite crystals. The resulting peptide–zeolite MLs were able to capture selectively α4β1 integrin-expressing cells. In perspective, the α4β1 integrin ligands identified in this study can find applications for preparing biofunctionalized surfaces and diagnostic devices to control the progression of α4β1 integrin-correlated diseases. Full article
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13 pages, 10786 KiB  
Article
Novel Biomimetic Human TLR2-Derived Peptides for Potential Targeting of Lipoteichoic Acid: An In Silico Assessment
by Nikita Devnarain, Ayman Y. Waddad, Beatriz G. de la Torre, Fernando Albericio and Thirumala Govender
Biomedicines 2021, 9(8), 1063; https://doi.org/10.3390/biomedicines9081063 - 21 Aug 2021
Cited by 1 | Viewed by 2152
Abstract
Antimicrobial resistance is one of the most significant threats to health and economy around the globe and has been compounded by the emergence of COVID-19, raising important consequences for antimicrobial resistance development. Contrary to conventional targeting approaches, the use of biomimetic application via [...] Read more.
Antimicrobial resistance is one of the most significant threats to health and economy around the globe and has been compounded by the emergence of COVID-19, raising important consequences for antimicrobial resistance development. Contrary to conventional targeting approaches, the use of biomimetic application via nanoparticles for enhanced cellular targeting, cell penetration and localized antibiotic delivery has been highlighted as a superior approach to identify novel targeting ligands for combatting antimicrobial resistance. Gram-positive bacterial cell walls contain lipoteichoic acid (LTA), which binds specifically to Toll-like receptor 2 (TLR2) on human macrophages. This phenomenon has the potential to be exploited for the design of biomimetic peptides for antibacterial application. In this study, we have derived peptides from sequences present in human TLR2 that bind to LTA with high affinity. In silico approaches including molecular modelling, molecular docking, molecular dynamics, and thermodynamics have enabled the identification of these crucial binding amino acids, the design of four novel biomimetic TLR2-derived peptides and their LTA binding potential. The outcomes of this study have revealed that one of these novel peptides binds to LTA more strongly and stably than the other three peptides and has the potential to enhance LTA targeting and bacterial cell penetration. Full article
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18 pages, 3038 KiB  
Article
HMP-S7 Is a Novel Anti-Leukemic Peptide Discovered from Human Milk
by Wararat Chiangjong, Jirawan Panachan, Thitinee Vanichapol, Nutkridta Pongsakul, Pongpak Pongphitcha, Teerapong Siriboonpiputtana, Tassanee Lerksuthirat, Pracha Nuntnarumit, Sarayut Supapannachart, Chantragan Srisomsap, Jisnuson Svasti, Suradej Hongeng and Somchai Chutipongtanate
Biomedicines 2021, 9(8), 981; https://doi.org/10.3390/biomedicines9080981 - 09 Aug 2021
Cited by 2 | Viewed by 2100
Abstract
Chemotherapy in childhood leukemia is associated with late morbidity in leukemic survivors, while certain patient subsets are relatively resistant to standard chemotherapy. It is therefore important to identify new agents with sensitivity and selectivity towards leukemic cells, while having less systemic toxicity. Peptide-based [...] Read more.
Chemotherapy in childhood leukemia is associated with late morbidity in leukemic survivors, while certain patient subsets are relatively resistant to standard chemotherapy. It is therefore important to identify new agents with sensitivity and selectivity towards leukemic cells, while having less systemic toxicity. Peptide-based therapeutics has gained a great deal of attention during the last few years. Here, we used an integrative workflow combining mass spectrometric peptide library construction, in silico anticancer peptide screening, and in vitro leukemic cell studies to discover a novel anti-leukemic peptide having 3+ charges and an alpha helical structure, namely HMP-S7, from human breast milk. HMP-S7 showed cytotoxic activity against four distinct leukemic cell lines in a dose-dependent manner but had no effect on solid malignancies or representative normal cells. HMP-S7 induced leukemic cell death by penetrating the plasma membrane to enter the cytoplasm and cause the leakage of lactate dehydrogenase, thus acting in a membranolytic manner. Importantly, HMP-S7 exhibited anti-leukemic effects against patient-derived leukemic cells ex vivo. In conclusion, HMP-S7 is a selective anti-leukemic peptide with promise, which requires further validation in preclinical and clinical studies. Full article
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Review

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37 pages, 21184 KiB  
Review
Discovery, Optimization, and Clinical Application of Natural Antimicrobial Peptides
by Armando A. Rodríguez, Anselmo Otero-González, Maretchia Ghattas and Ludger Ständker
Biomedicines 2021, 9(10), 1381; https://doi.org/10.3390/biomedicines9101381 - 03 Oct 2021
Cited by 24 | Viewed by 4443
Abstract
Antimicrobial peptides (AMPs) are widespread in multicellular organisms. These structurally diverse molecules are produced as the first line of defense against pathogens such as bacteria, viruses, fungi, and parasites. Also known as host defense peptides in higher eukaryotic organisms, AMPs display immunomodulatory and [...] Read more.
Antimicrobial peptides (AMPs) are widespread in multicellular organisms. These structurally diverse molecules are produced as the first line of defense against pathogens such as bacteria, viruses, fungi, and parasites. Also known as host defense peptides in higher eukaryotic organisms, AMPs display immunomodulatory and anticancer activities. During the last 30 years, technological advances have boosted the research on antimicrobial peptides, which have also attracted great interest as an alternative to tackling the antimicrobial resistance scenario mainly provoked by some bacterial and fungal pathogens. However, the introduction of natural AMPs in clinical trials faces challenges such as proteolytic digestion, short half-lives, and cytotoxicity upon systemic and oral application. Therefore, some strategies have been implemented to improve the properties of AMPs aiming to be used as effective therapeutic agents. In the present review, we summarize the discovery path of AMPs, focusing on preclinical development, recent advances in chemical optimization and peptide delivery systems, and their introduction into the market. Full article
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