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Membrane–Peptide Interactions: From Basics to Current Applications

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

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 55186

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Special Issue Editors

Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Interests: dengue virus; Zika virus; West Nile virus; HIV; viral entry inhibitors; broad-spectrum antivirals; antimicrobial peptides; antiviral peptides; biophysics; nanomedicine
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Special Issue Information

Dear Colleagues,

Natural and synthetic membrane active peptides have been gaining increasing interest during the last decades. Their attractiveness for researchers relies, among other factors, on their biological role in host defense and their wide potential in multiple disciplines, with a special focus on the medical field. Understanding the determinants for peptide–membrane interactions may enhance the knowledge of biomembrane functions such as membrane transport, fusion, and signaling processes, and it may bring some light on potential applications of peptides, as well as improve their design, contributing to the development of new agents for highly relevant applications, ranging from disease treatment to agricultural use.

Some key questions regarding peptide–membrane interactions remain to be answered. To address this question, the integration of multilateral approaches has been necessary, including biological, physical, and chemical approaches. This Special Issue aims to cover recent scientific contributions to the interaction of different types of peptide obtained from different sources (e.g., plants, animals, and fungus, as well as in silico designed) with cell membranes, as well as review articles addressing the current advances and state-of-the-art in this multidisciplinary field.

Potential topics include but are not limited to the following:

  • Peptide structure and function;
  • Antimicrobial peptides, anticancer peptides, cell-penetrating peptides, glycopeptides, cyclic peptides, and synthetic peptides;
  • Peptide formulations and their delivery;
  • Basic determinants for peptide–membrane interactions;
  • Peptide–membrane interactions in health and disease;
  • Therapeutic and biotech applications;
  • Computational modeling.

Assoc. Prof. Nuno C. Santos
Dr. Sónia Gonçalves
Guest Editors

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Keywords

  • Bioactive peptides
  • Therapeutics
  • Computational modeling
  • Peptide–membrane interactions
  • Lipid vesicles
  • Membrane models
  • Membrane probes
  • Drug delivery
  • Spectroscopy
  • Microscopy

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Published Papers (17 papers)

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26 pages, 7159 KiB  
Article
Membrane Association Modes of Natural Anticancer Peptides: Mechanistic Details on Helicity, Orientation, and Surface Coverage
by Mayra Quemé-Peña, Tünde Juhász, Gergely Kohut, Maria Ricci, Priyanka Singh, Imola Cs. Szigyártó, Zita I. Papp, Lívia Fülöp and Tamás Beke-Somfai
Int. J. Mol. Sci. 2021, 22(16), 8613; https://doi.org/10.3390/ijms22168613 - 10 Aug 2021
Cited by 7 | Viewed by 2794
Abstract
Anticancer peptides (ACPs) could potentially offer many advantages over other cancer therapies. ACPs often target cell membranes, where their surface mechanism is coupled to a conformational change into helical structures. However, details on their binding are still unclear, which would be crucial to [...] Read more.
Anticancer peptides (ACPs) could potentially offer many advantages over other cancer therapies. ACPs often target cell membranes, where their surface mechanism is coupled to a conformational change into helical structures. However, details on their binding are still unclear, which would be crucial to reach progress in connecting structural aspects to ACP action and to therapeutic developments. Here we investigated natural helical ACPs, Lasioglossin LL-III, Macropin 1, Temporin-La, FK-16, and LL-37, on model liposomes, and also on extracellular vesicles (EVs), with an outer leaflet composition similar to cancer cells. The combined simulations and experiments identified three distinct binding modes to the membranes. Firstly, a highly helical structure, lying mainly on the membrane surface; secondly, a similar, yet only partially helical structure with disordered regions; and thirdly, a helical monomeric form with a non-inserted perpendicular orientation relative to the membrane surface. The latter allows large swings of the helix while the N-terminal is anchored to the headgroup region. These results indicate that subtle differences in sequence and charge can result in altered binding modes. The first two modes could be part of the well-known carpet model mechanism, whereas the newly identified third mode could be an intermediate state, existing prior to membrane insertion. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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35 pages, 13314 KiB  
Article
Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and Glioblastoma
by Theresa Maxian, Lisa Gerlitz, Sabrina Riedl, Beate Rinner and Dagmar Zweytick
Int. J. Mol. Sci. 2021, 22(16), 8469; https://doi.org/10.3390/ijms22168469 - 06 Aug 2021
Cited by 9 | Viewed by 1992
Abstract
The study investigates the antitumor effect of two cationic peptides, R-DIM-P-LF11-215 (RDP215) and the D-amino acid variant 9D-R-DIM-P-LF11-215 (9D-RDP215), targeting the negatively charged lipid phosphatidylserine (PS) exposed by cancer cells, such as of melanoma and glioblastoma. Model studies mimicking cancer and non-cancer membranes [...] Read more.
The study investigates the antitumor effect of two cationic peptides, R-DIM-P-LF11-215 (RDP215) and the D-amino acid variant 9D-R-DIM-P-LF11-215 (9D-RDP215), targeting the negatively charged lipid phosphatidylserine (PS) exposed by cancer cells, such as of melanoma and glioblastoma. Model studies mimicking cancer and non-cancer membranes revealed the specificity for the cancer-mimic PS by both peptides with a slightly stronger impact by the D-peptide. Accordingly, membrane effects studied by DSC, leakage and quenching experiments were solely induced by the peptides when the cancer mimic PS was present. Circular dichroism revealed a sole increase in β-sheet conformation in the presence of the cancer mimic for both peptides; only 9D-RDP215 showed increased structure already in the buffer. Ex vitro stability studies by SDS-PAGE as well as in vitro with melanoma A375 revealed a stabilizing effect of D-amino acids in the presence of serum, which was also confirmed in 2D and 3D in vitro experiments on glioblastoma LN-229. 9D-RDP215 was additionally able to pass a BBB model, whereupon it induced significant levels of cell death in LN-229 spheroids. Summarized, the study encourages the introduction of D-amino acids in the design of antitumor peptides for the improvement of their stable antitumor activity. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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15 pages, 2707 KiB  
Article
A Novel Peptide Derived from the Transmembrane Domain of Romo1 Is a Promising Candidate for Sepsis Treatment and Multidrug-Resistant Bacteria
by Deok-Gyun You, Hye-Ra Lee, Hong-Kyu Kim, Gi-Young Lee and Young-Do Yoo
Int. J. Mol. Sci. 2021, 22(15), 8243; https://doi.org/10.3390/ijms22158243 - 31 Jul 2021
Cited by 2 | Viewed by 1761
Abstract
The emergence of multidrug-resistant (MDR) bacteria through the abuse and long-term use of antibiotics is a serious health problem worldwide. Therefore, novel antimicrobial agents that can cure an infection from MDR bacteria, especially gram-negative bacteria, are urgently needed. Antimicrobial peptides, part of the [...] Read more.
The emergence of multidrug-resistant (MDR) bacteria through the abuse and long-term use of antibiotics is a serious health problem worldwide. Therefore, novel antimicrobial agents that can cure an infection from MDR bacteria, especially gram-negative bacteria, are urgently needed. Antimicrobial peptides, part of the innate immunity system, have been studied to find bactericidal agents potent against MDR bacteria. However, they have many problems, such as restrained systemic activity and cytotoxicity. In a previous study, we suggested that the K58–R78 domain of Romo1, a mitochondrial protein encoded by the nucleus, was a promising treatment candidate for sepsis caused by MDR bacteria. Here, we performed sequence optimization to enhance the antimicrobial activity of this peptide and named it as AMPR-22 (antimicrobial peptide derived from Romo1). It showed broad-spectrum antimicrobial activity against 17 sepsis-causing bacteria, including MDR strains, by inducing membrane permeabilization. Moreover, treatment with AMPR-22 enabled a remarkable survival rate in mice injected with MDR bacteria in a murine model of sepsis. Based on these results, we suggest that AMPR-22 could be prescribed as a first-line therapy (prior to bacterial identification) for patients diagnosed with sepsis. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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18 pages, 4334 KiB  
Article
A Synthetic Cell-Penetrating Heparin-Binding Peptide Derived from BMP4 with Anti-Inflammatory and Chondrogenic Functions for the Treatment of Arthritis
by Da Hyeon Choi, Dongwoo Lee, Beom Soo Jo, Kwang-Sook Park, Kyeong Eun Lee, Ju Kwang Choi, Yoon Jeong Park, Jue-Yeon Lee and Yoon Shin Park
Int. J. Mol. Sci. 2020, 21(12), 4251; https://doi.org/10.3390/ijms21124251 - 15 Jun 2020
Cited by 7 | Viewed by 2494
Abstract
We report dual therapeutic effects of a synthetic heparin-binding peptide (HBP) corresponding to residues 15–24 of the heparin binding site in BMP4 in a collagen-induced rheumatic arthritis model (CIA) for the first time. The cell penetrating capacity of HBP led to improved cartilage [...] Read more.
We report dual therapeutic effects of a synthetic heparin-binding peptide (HBP) corresponding to residues 15–24 of the heparin binding site in BMP4 in a collagen-induced rheumatic arthritis model (CIA) for the first time. The cell penetrating capacity of HBP led to improved cartilage recovery and anti-inflammatory effects via down-regulation of the iNOS-IFNγ-IL6 signaling pathway in inflamed RAW264.7 cells. Both arthritis and paw swelling scores were significantly improved following HBP injection into CIA model mice. Anti-rheumatic effects were accelerated upon combined treatment with Enbrel® and HBP. Serum IFNγ and IL6 concentrations were markedly reduced following intraperitoneal HBP injection in CIA mice. The anti-rheumatic effects of HBP in mice were similar to those of Enbrel®. Furthermore, the combination of Enbrel® and HBP induced similar anti-rheumatic and anti-inflammatory effects as Enbrel®. We further investigated the effect of HBP on damaged chondrocytes in CIA mice. Regenerative capacity of HBP was confirmed based on increased expression of chondrocyte biomarker genes, including aggrecan, collagen type II and TNFα, in adult human knee chondrocytes. These findings collectively support the utility of our cell-permeable bifunctional HBP with anti-inflammatory and chondrogenic properties as a potential source of therapeutic agents for degenerative inflammatory diseases. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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24 pages, 6231 KiB  
Article
Pisum sativum Defensin 1 Eradicates Mouse Metastatic Lung Nodules from B16F10 Melanoma Cells
by Virginia Sara Grancieri do Amaral, Stephanie Alexia Cristina Silva Santos, Paula Cavalcante de Andrade, Jenifer Nowatzki, Nilton Silva Júnior, Luciano Neves de Medeiros, Lycia Brito Gitirana, Pedro Geraldo Pascutti, Vitor H. Almeida, Robson Q. Monteiro and Eleonora Kurtenbach
Int. J. Mol. Sci. 2020, 21(8), 2662; https://doi.org/10.3390/ijms21082662 - 11 Apr 2020
Cited by 5 | Viewed by 3079
Abstract
Psd1 is a pea plant defensin which can be actively expressed in Pichia pastoris and shows broad antifungal activity. This activity is dependent on fungal membrane glucosylceramide (GlcCer), which is also important for its internalization, nuclear localization, and endoreduplication. Certain cancer cells [...] Read more.
Psd1 is a pea plant defensin which can be actively expressed in Pichia pastoris and shows broad antifungal activity. This activity is dependent on fungal membrane glucosylceramide (GlcCer), which is also important for its internalization, nuclear localization, and endoreduplication. Certain cancer cells present a lipid metabolism imbalance resulting in the overexpression of GlcCer in their membrane. In this work, in vitroassays using B16F10 cells showed that labeled fluorescein isothiocyanate FITC-Psd1 internalized into live cultured cells and targeted the nucleus, which underwent fragmentation, exhibiting approximately 60% of cells in the sub-G0/G1 stage. This phenomenon was dependent on GlcCer, and the participation of cyclin-F was suggested. In a murine lung metastatic melanoma model, intravenous injection of Psd1 together with B16F10 cells drastically reduced the number of nodules at concentrations above 0.5 mg/kg. Additionally, the administration of 1 mg/kg Psd1 decreased the number of lung inflammatory cells to near zero without weight loss, unlike animals that received melanoma cells only. It is worth noting that 1 mg/kg Psd1 alone did not provoke inflammation in lung tissue or weight or vital signal losses over 21 days, inferring no whole animal cytotoxicity. These results suggest that Psd1 could be a promising prototype for human lung anti-metastatic melanoma therapy. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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18 pages, 3655 KiB  
Article
Drug Conjugation Induced Modulation of Structural and Membrane Interaction Features of Cationic Cell-Permeable Peptides
by Edit Pári, Kata Horváti, Szilvia Bősze, Beáta Biri-Kovács, Bálint Szeder, Ferenc Zsila and Éva Kiss
Int. J. Mol. Sci. 2020, 21(6), 2197; https://doi.org/10.3390/ijms21062197 - 22 Mar 2020
Cited by 4 | Viewed by 2597
Abstract
Cell-penetrating peptides might have great potential for enhancing the therapeutic effect of drug molecules against such dangerous pathogens as Mycobacterium tuberculosis (Mtb), which causes a major health problem worldwide. A set of cationic cell-penetration peptides with various hydrophobicity were selected and synthesized as [...] Read more.
Cell-penetrating peptides might have great potential for enhancing the therapeutic effect of drug molecules against such dangerous pathogens as Mycobacterium tuberculosis (Mtb), which causes a major health problem worldwide. A set of cationic cell-penetration peptides with various hydrophobicity were selected and synthesized as drug carrier of isoniazid (INH), a first-line antibacterial agent against tuberculosis. Molecular interactions between the peptides and their INH-conjugates with cell-membrane-forming lipid layers composed of DPPC and mycolic acid (a characteristic component of Mtb cell wall) were evaluated, using the Langmuir balance technique. Secondary structure of the INH conjugates was analyzed and compared to that of the native peptides by circular dichroism spectroscopic experiments performed in aqueous and membrane mimetic environment. A correlation was found between the conjugation induced conformational and membrane affinity changes of the INH–peptide conjugates. The degree and mode of interaction were also characterized by AFM imaging of penetrated lipid layers. In vitro biological evaluation was performed with Penetratin and Transportan conjugates. Results showed similar internalization rate into EBC-1 human squamous cell carcinoma, but markedly different subcellular localization and activity on intracellular Mtb. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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19 pages, 4032 KiB  
Article
Structural Analysis and Design of Chionodracine-Derived Peptides Using Circular Dichroism and Molecular Dynamics Simulations
by Stefano Borocci, Giulia Della Pelle, Francesca Ceccacci, Cristina Olivieri, Francesco Buonocore and Fernando Porcelli
Int. J. Mol. Sci. 2020, 21(4), 1401; https://doi.org/10.3390/ijms21041401 - 19 Feb 2020
Cited by 3 | Viewed by 2301
Abstract
Antimicrobial peptides have been identified as one of the alternatives to the extensive use of common antibiotics as they show a broad spectrum of activity against human pathogens. Among these is Chionodracine (Cnd), a host-defense peptide isolated from the Antarctic icefish [...] Read more.
Antimicrobial peptides have been identified as one of the alternatives to the extensive use of common antibiotics as they show a broad spectrum of activity against human pathogens. Among these is Chionodracine (Cnd), a host-defense peptide isolated from the Antarctic icefish Chionodraco hamatus, which belongs to the family of Piscidins. Previously, we demonstrated that Cnd and its analogs display high antimicrobial activity against ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species). Herein, we investigate the interactions with lipid membranes of Cnd and two analogs, Cnd-m3 and Cnd-m3a, showing enhanced potency. Using a combination of Circular Dichroism, fluorescence spectroscopy, and all-atom Molecular Dynamics (MD) simulations, we determined the structural basis for the different activity among these peptides. We show that all peptides are predominantly unstructured in water and fold, preferentially as α-helices, in the presence of lipid vesicles of various compositions. Through a series of MD simulations of 400 ns time scale, we show the effect of mutations on the structure and lipid interactions of Cnd and its analogs. By explaining the structural basis for the activity of these analogs, our findings provide structural templates to design minimalistic peptides for therapeutics. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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19 pages, 2157 KiB  
Article
Novel ACE Inhibitory Peptides Derived from Simulated Gastrointestinal Digestion in Vitro of Sesame (Sesamum indicum L.) Protein and Molecular Docking Study
by Ruidan Wang, Xin Lu, Qiang Sun, Jinhong Gao, Lin Ma and Jinian Huang
Int. J. Mol. Sci. 2020, 21(3), 1059; https://doi.org/10.3390/ijms21031059 - 05 Feb 2020
Cited by 50 | Viewed by 4107
Abstract
The aim of this study was to isolate and identify angiotensin I-converting enzyme (ACE) inhibitory peptides from sesame protein through simulated gastrointestinal digestion in vitro, and to explore the underlying mechanisms by molecular docking. The sesame protein was enzymatically hydrolyzed by pepsin, trypsin, [...] Read more.
The aim of this study was to isolate and identify angiotensin I-converting enzyme (ACE) inhibitory peptides from sesame protein through simulated gastrointestinal digestion in vitro, and to explore the underlying mechanisms by molecular docking. The sesame protein was enzymatically hydrolyzed by pepsin, trypsin, and α-chymotrypsin. The degree of hydrolysis (DH) and peptide yield increased with the increase of digest time. Moreover, ACE inhibitory activity was enhanced after digestion. The sesame protein digestive solution (SPDS) was purified by ultrafiltration through different molecular weight cut-off (MWCO) membranes and SPDS-VII (< 3 kDa) had the strongest ACE inhibition. SPDS-VII was further purified by NGC Quest™ 10 Plus Chromatography System and finally 11 peptides were identified by Nano UHPLC-ESI-MS/MS (nano ultra-high performance liquid chromatography-electrospray ionization mass spectrometry/mass spectrometry) from peak 4. The peptide GHIITVAR from 11S globulin displayed the strongest ACE inhibitory activity (IC50 = 3.60 ± 0.10 μM). Furthermore, the docking analysis revealed that the ACE inhibition of GHIITVAR was mainly attributed to forming very strong hydrogen bonds with the active sites of ACE. These results identify sesame protein as a rich source of ACE inhibitory peptides and further indicate that GHIITVAR has the potential for development of new functional foods. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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26 pages, 11530 KiB  
Article
Characterization and Identification of Natural Antimicrobial Peptides on Different Organisms
by Chia-Ru Chung, Jhih-Hua Jhong, Zhuo Wang, Siyu Chen, Yu Wan, Jorng-Tzong Horng and Tzong-Yi Lee
Int. J. Mol. Sci. 2020, 21(3), 986; https://doi.org/10.3390/ijms21030986 - 02 Feb 2020
Cited by 46 | Viewed by 4133
Abstract
Because of the rapid development of multidrug resistance, conventional antibiotics cannot kill pathogenic bacteria efficiently. New antibiotic treatments such as antimicrobial peptides (AMPs) can provide a possible solution to the antibiotic-resistance crisis. However, the identification of AMPs using experimental methods is expensive and [...] Read more.
Because of the rapid development of multidrug resistance, conventional antibiotics cannot kill pathogenic bacteria efficiently. New antibiotic treatments such as antimicrobial peptides (AMPs) can provide a possible solution to the antibiotic-resistance crisis. However, the identification of AMPs using experimental methods is expensive and time-consuming. Meanwhile, few studies use amino acid compositions (AACs) and physicochemical properties with different sequence lengths against different organisms to predict AMPs. Therefore, the major purpose of this study is to identify AMPs on seven categories of organisms, including amphibians, humans, fish, insects, plants, bacteria, and mammals. According to the one-rule attribute evaluation, the selected features were used to construct the predictive models based on the random forest algorithm. Compared to the accuracies of iAMP-2L (a web-server for identifying AMPs and their functional types), ADAM (a database of AMP), and MLAMP (a multi-label AMP classifier), the proposed method yielded higher than 92% in predicting AMPs on each category. Additionally, the sensitivities of the proposed models in the prediction of AMPs of seven organisms were higher than that of all other tools. Furthermore, several physicochemical properties (charge, hydrophobicity, polarity, polarizability, secondary structure, normalized van der Waals volume, and solvent accessibility) of AMPs were investigated according to their sequence lengths. As a result, the proposed method is a practical means to complement the existing tools in the characterization and identification of AMPs in different organisms. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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22 pages, 3642 KiB  
Article
Lipidated Analogs of the LL-37-Derived Peptide Fragment KR12—Structural Analysis, Surface-Active Properties and Antimicrobial Activity
by Elżbieta Kamysz, Emilia Sikorska, Maciej Jaśkiewicz, Marta Bauer, Damian Neubauer, Sylwia Bartoszewska, Wioletta Barańska-Rybak and Wojciech Kamysz
Int. J. Mol. Sci. 2020, 21(3), 887; https://doi.org/10.3390/ijms21030887 - 30 Jan 2020
Cited by 47 | Viewed by 3743
Abstract
An increasing number of multidrug-resistant pathogens is a serious problem of modern medicine and new antibiotics are highly demanded. In this study, different n-alkyl acids (C2-C14) and aromatic acids (benzoic and trans-cinnamic) were conjugated to the N-terminus [...] Read more.
An increasing number of multidrug-resistant pathogens is a serious problem of modern medicine and new antibiotics are highly demanded. In this study, different n-alkyl acids (C2-C14) and aromatic acids (benzoic and trans-cinnamic) were conjugated to the N-terminus of KR12 amide. The effect of this modification on antimicrobial activity (ESKAPE bacteria and biofilm of Staphylococcus aureus) and cytotoxicity (human red blood cells and HaCaT cell line) was examined. The effect of lipophilic modifications on helicity was studied by CD spectroscopy, whereas peptide self-assembly was studied by surface tension measurements and NMR spectroscopy. As shown, conjugation of the KR12-NH2 peptide with C4-C14 fatty acid chains enhanced the antimicrobial activity with an optimum demonstrated by C8-KR12-NH2 (MIC 1–4 μg/mL against ESKAPE strains; MBEC of S. aureus 4–16 μg/mL). Correlation between antimicrobial activity and self-assembly behavior of C14-KR12-NH2 and C8-KR12-NH2 has shown that the former self-assembled into larger aggregated structures, which reduced its antimicrobial activity. In conclusion, N-terminal modification can enhance antimicrobial activity of KR12-NH2; however, at the same time, the cytotoxicity increases. It seems that the selectivity against pathogens over human cells can be achieved through conjugation of peptide N-terminus with appropriate n-alkyl fatty and aromatic acids. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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20 pages, 3329 KiB  
Article
Revisiting the Interaction of Melittin with Phospholipid Bilayers: The Effects of Concentration and Ionic Strength
by Thiru Sabapathy, Evelyne Deplazes and Ricardo L. Mancera
Int. J. Mol. Sci. 2020, 21(3), 746; https://doi.org/10.3390/ijms21030746 - 23 Jan 2020
Cited by 16 | Viewed by 3498
Abstract
Melittin is an anti-microbial peptide (AMP) and one of the most studied membrane-disrupting peptides. There is, however, a lack of accurate measurements of the concentration-dependent kinetics and affinity of binding of melittin to phospholipid membranes. In this study, we used surface plasmon resonance [...] Read more.
Melittin is an anti-microbial peptide (AMP) and one of the most studied membrane-disrupting peptides. There is, however, a lack of accurate measurements of the concentration-dependent kinetics and affinity of binding of melittin to phospholipid membranes. In this study, we used surface plasmon resonance spectroscopy to determine the concentration-dependent effect on the binding of melittin to 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) bilayers in vesicles. Three concentration ranges were considered, and when combined, covered two orders of magnitudes (0.04 µM to 8 µM), corresponding to concentrations relevant to the membrane-disrupting and anti-microbial activities of melittin. Binding kinetics data were analysed using a 1:1 Langmuir-binding model and a two-state reaction model. Using in-depth quantitative analysis, we characterised the effect of peptide concentration, the addition of NaCl at physiological ionic strength and the choice of kinetic binding model on the reliability of the calculated kinetics and affinity of binding parameters. The apparent binding affinity of melittin for POPC bilayers was observed to decrease with increasing peptide/lipid (P/L) ratio, primarily due to the marked decrease in the association rate. At all concentration ranges, the two-state reaction model provided a better fit to the data and, thus, a more reliable estimate of binding affinity. Addition of NaCl significantly reduced the signal response during the association phase; however, no substantial effect on the binding affinity of melittin to the POPC bilayers was observed. These findings based on POPC bilayers could have important implications for our understanding of the mechanism of action of melittin on more complex model cell membranes of higher physiological relevance. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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13 pages, 3658 KiB  
Article
Modification of Luffa Sponge for Enrichment of Phosphopeptides
by Lili Dai, Zhe Sun and Ping Zhou
Int. J. Mol. Sci. 2020, 21(1), 101; https://doi.org/10.3390/ijms21010101 - 22 Dec 2019
Cited by 3 | Viewed by 2326
Abstract
The enrichment technique is crucial to the comprehensive analysis of protein phosphorylation. In this work, a facile, green and efficient synthetic method was set up for quaternization of luffa sponge. The resultant luffa sponge showed strong anion-exchange characteristics and a high adsorption ability [...] Read more.
The enrichment technique is crucial to the comprehensive analysis of protein phosphorylation. In this work, a facile, green and efficient synthetic method was set up for quaternization of luffa sponge. The resultant luffa sponge showed strong anion-exchange characteristics and a high adsorption ability for phosphate ions. Along with the unique physical properties, e.g., tenacity and porous texture, quaternized luffa sponge was demonstrated to be a well-suited solid-phase extraction (SPE) material. The quaternized luffa sponge-based SPE method was simple, cost-effective and convenient in operation, and was successfully applied to the capture of phosphopeptides from protein digests. The enrichment approach exhibited exceptionally high selectivity, sensitivity and strong anti-interference ability. Four phosphopeptides were still detected by using the digest mixture of β-casein and bovine serum albumin with a molar ratio of 1:100. 21 phosphopeptides were identified from the tryptic digest of non-fat milk. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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11 pages, 1239 KiB  
Article
Synthetic Human β Defensin-3-C15 Peptide in Endodontics: Potential Therapeutic Agent in Streptococcus gordonii Lipoprotein-Stimulated Human Dental Pulp-Derived Cells
by Yeon-Jee Yoo, Hiran Perinpanayagam, Jue-Yeon Lee, Soram Oh, Yu Gu, A-Reum Kim, Seok-Woo Chang, Seung-Ho Baek and Kee-Yeon Kum
Int. J. Mol. Sci. 2020, 21(1), 71; https://doi.org/10.3390/ijms21010071 - 20 Dec 2019
Cited by 5 | Viewed by 2954
Abstract
Human β defensin-3-C15, an epithelium-derived cationic peptide that has antibacterial/antifungal and immuno-regulatory properties, is getting attention as potential therapeutic agent in endodontics. This study aimed to investigate if synthetic human β defensin-3-C15 (HBD3-C15) peptides could inhibit inflammatory responses in human dental pulp cells [...] Read more.
Human β defensin-3-C15, an epithelium-derived cationic peptide that has antibacterial/antifungal and immuno-regulatory properties, is getting attention as potential therapeutic agent in endodontics. This study aimed to investigate if synthetic human β defensin-3-C15 (HBD3-C15) peptides could inhibit inflammatory responses in human dental pulp cells (hDPCs), which had been induced by gram-positive endodontic pathogen. hDPC explant cultures were stimulated with Streptococcus gordonii lipoprotein extracts for 24 h to induce expression of pro-inflammatory mediators. The cells were then treated with either HBD3-C15 (50 μg/mL) or calcium hydroxide (CH, 100 μg/mL) as control for seven days, to assess their anti-inflammatory effects. Quantitative RT-PCR analyses and multiplex assays showed that S. gordonii lipoprotein induced the inflammatory reaction in hDPCs. There was a significant reduction of IL-8 and MCP-1 within 24 h of treatment with either CH or HBD3-C15 (p < 0.05), which was sustained over 1 week of treatment. Alleviation of inflammation in both medications was related to COX-2 expression and PGE2 secretion (p < 0.05), rather than TLR2 changes (p > 0.05). These findings demonstrate comparable effects of CH and HDB3-C15 as therapeutic agents for inflamed hDPCs. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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21 pages, 3768 KiB  
Article
Biophysical Insight on the Membrane Insertion of an Arginine-Rich Cell-Penetrating Peptide
by Marie-Lise Jobin, Lydie Vamparys, Romain Deniau, Axelle Grélard, Cameron D. Mackereth, Patrick F.J. Fuchs and Isabel D. Alves
Int. J. Mol. Sci. 2019, 20(18), 4441; https://doi.org/10.3390/ijms20184441 - 09 Sep 2019
Cited by 13 | Viewed by 2952
Abstract
Cell-penetrating peptides (CPPs) are short peptides that can translocate and transport cargoes into the intracellular milieu by crossing biological membranes. The mode of interaction and internalization of cell-penetrating peptides has long been controversial. While their interaction with anionic membranes is quite well understood, [...] Read more.
Cell-penetrating peptides (CPPs) are short peptides that can translocate and transport cargoes into the intracellular milieu by crossing biological membranes. The mode of interaction and internalization of cell-penetrating peptides has long been controversial. While their interaction with anionic membranes is quite well understood, the insertion and behavior of CPPs in zwitterionic membranes, a major lipid component of eukaryotic cell membranes, is poorly studied. Herein, we investigated the membrane insertion of RW16 into zwitterionic membranes, a versatile CPP that also presents antibacterial and antitumor activities. Using complementary approaches, including NMR spectroscopy, fluorescence spectroscopy, circular dichroism, and molecular dynamic simulations, we determined the high-resolution structure of RW16 and measured its membrane insertion and orientation properties into zwitterionic membranes. Altogether, these results contribute to explaining the versatile properties of this peptide toward zwitterionic lipids. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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19 pages, 4448 KiB  
Article
Accelerated Molecular Dynamics Applied to the Peptaibol Folding Problem
by Chetna Tyagi, Tamás Marik, Csaba Vágvölgyi, László Kredics and Ferenc Ötvös
Int. J. Mol. Sci. 2019, 20(17), 4268; https://doi.org/10.3390/ijms20174268 - 30 Aug 2019
Cited by 16 | Viewed by 3107 | Correction
Abstract
The use of enhanced sampling molecular dynamics simulations to facilitate the folding of proteins is a relatively new approach which has quickly gained momentum in recent years. Accelerated molecular dynamics (aMD) can elucidate the dynamic path from the unfolded state to the near-native [...] Read more.
The use of enhanced sampling molecular dynamics simulations to facilitate the folding of proteins is a relatively new approach which has quickly gained momentum in recent years. Accelerated molecular dynamics (aMD) can elucidate the dynamic path from the unfolded state to the near-native state, “flattened” by introducing a non-negative boost to the potential. Alamethicin F30/3 (Alm F30/3), chosen in this study, belongs to the class of peptaibols that are 7–20 residue long, non-ribosomally synthesized, amphipathic molecules that show interesting membrane perturbing activity. The recent studies undertaken on the Alm molecules and their transmembrane channels have been reviewed. Three consecutive simulations of ~900 ns each were carried out where N-terminal folding could be observed within the first 100 ns, while C-terminal folding could only be achieved almost after 800 ns. It took ~1 μs to attain the near-native conformation with stronger potential boost which may take several μs worth of classical MD to produce the same results. The Alm F30/3 hexamer channel was also simulated in an E. coli mimicking membrane under an external electric field that correlates with previous experiments. It can be concluded that aMD simulation techniques are suited to elucidate peptaibol structures and to understand their folding dynamics. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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25 pages, 3097 KiB  
Article
Characterization of Tachyplesin Peptides and Their Cyclized Analogues to Improve Antimicrobial and Anticancer Properties
by Felicitas Vernen, Peta J. Harvey, Susana A. Dias, Ana Salomé Veiga, Yen-Hua Huang, David J. Craik, Nicole Lawrence and Sónia Troeira Henriques
Int. J. Mol. Sci. 2019, 20(17), 4184; https://doi.org/10.3390/ijms20174184 - 26 Aug 2019
Cited by 35 | Viewed by 4499
Abstract
Tachyplesin I, II and III are host defense peptides from horseshoe crab species with antimicrobial and anticancer activities. They have an amphipathic β-hairpin structure, are highly positively-charged and differ by only one or two amino acid residues. In this study, we compared the [...] Read more.
Tachyplesin I, II and III are host defense peptides from horseshoe crab species with antimicrobial and anticancer activities. They have an amphipathic β-hairpin structure, are highly positively-charged and differ by only one or two amino acid residues. In this study, we compared the structure and activity of the three tachyplesin peptides alongside their backbone cyclized analogues. We assessed the peptide structures using nuclear magnetic resonance (NMR) spectroscopy, then compared the activity against bacteria (both in the planktonic and biofilm forms) and a panel of cancerous cells. The importance of peptide-lipid interactions was examined using surface plasmon resonance and fluorescence spectroscopy methodologies. Our studies showed that tachyplesin peptides and their cyclic analogues were most potent against Gram-negative bacteria and melanoma cell lines, and showed a preference for binding to negatively-charged lipid membranes. Backbone cyclization did not improve potency, but improved peptide stability in human serum and reduced toxicity toward human red blood cells. Peptide-lipid binding affinity, orientation within the membrane, and ability to disrupt lipid bilayers differed between the cyclized peptide and the parent counterpart. We show that tachyplesin peptides and cyclized analogues have similarly potent antimicrobial and anticancer properties, but that backbone cyclization improves their stability and therapeutic potential. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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Review

Jump to: Research

23 pages, 1072 KiB  
Review
Non-Lytic Antibacterial Peptides That Translocate Through Bacterial Membranes to Act on Intracellular Targets
by Marlon H. Cardoso, Beatriz T. Meneguetti, Bruna O. Costa, Danieli F. Buccini, Karen G. N. Oshiro, Sergio L. E. Preza, Cristiano M. E. Carvalho, Ludovico Migliolo and Octávio L. Franco
Int. J. Mol. Sci. 2019, 20(19), 4877; https://doi.org/10.3390/ijms20194877 - 01 Oct 2019
Cited by 63 | Viewed by 5869
Abstract
The advent of multidrug resistance among pathogenic bacteria has attracted great attention worldwide. As a response to this growing challenge, diverse studies have focused on the development of novel anti-infective therapies, including antimicrobial peptides (AMPs). The biological properties of this class of antimicrobials [...] Read more.
The advent of multidrug resistance among pathogenic bacteria has attracted great attention worldwide. As a response to this growing challenge, diverse studies have focused on the development of novel anti-infective therapies, including antimicrobial peptides (AMPs). The biological properties of this class of antimicrobials have been thoroughly investigated, and membranolytic activities are the most reported mechanisms by which AMPs kill bacteria. Nevertheless, an increasing number of works have pointed to a different direction, in which AMPs are seen to be capable of displaying non-lytic modes of action by internalizing bacterial cells. In this context, this review focused on the description of the in vitro and in vivo antibacterial and antibiofilm activities of non-lytic AMPs, including indolicidin, buforin II PR-39, bactenecins, apidaecin, and drosocin, also shedding light on how AMPs interact with and further translocate through bacterial membranes to act on intracellular targets, including DNA, RNA, cell wall and protein synthesis. Full article
(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)
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