Biological Membrane and Bioactive Compounds Interactions

A special issue of Membranes (ISSN 2077-0375). This special issue belongs to the section "Biological Membrane Functions".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 15250

Special Issue Editors


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Guest Editor
Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland
Interests: medicinal chemistry; lipid bilayers; model membranes; cancer chemoprevention; new drug-like compounds—their design and physicochemical properties; together with their interactions with model lipid membranes
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Guest Editor
Department of Basic Chemical Sciences, Faculty of Pharmacy, Wroclaw Medical University, 50-367 Wrocław, Poland
Interests: molecular modeling; anti-inflammatory drugs; drug design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The interaction of drugs, as well as, natural bioactive compounds, with biological membranes is a complex and pharmacologically extremely important process. Drugs must cross biological membranes in order to be absorbed, and then undergo processes of distribution, metabolism and finally excretion. Moreover, enzymes, which may be membrane-bound proteins, are molecular targets of many drugs therefore pharmacological actions of different drugs may be a consequence of their direct interaction with proteins. There are also reports that some alternative mechanisms of action such as the chemoprevention of bioactive compounds e.g. non-steroidal anti-inflammatory drugs (NSAIDs) or flavonoids, may also be related to their interaction with the biological membranes and specific membrane proteins. Changes induced in lipid phase, such as an alteration of membrane curvature and phase behavior may in consequence also indirectly modify a conformation of membrane proteins. An interesting type of molecular interaction is also the interaction of surfactants with proteins as well as with the membranes themselves, because some types of surfactants can also be used in the design of new types of drugs e.g. in lysosome-targeting anti-cancer drugs. For that reason the investigation of bioactive compounds-membrane interactions is essential for understanding of molecular mechanisms of their action.

This Special Issue aims to investigate all types of bioactive compounds–membranes interactions. We are pleased to invite you to submit your original research articles as well as reviews. Research areas may include (but are not limited to) the following topics related to interactions of bioactive compounds with :

  • cellular membrane, and their influence on membrane structure, function and biomolecular organization and dynamics, fluidity and composition,
  • model membranes and liposomes,
  • membrane proteins, membrane traffic, receptors, and channels.

Both molecular modeling and simulation as well as biophysical (e.g. differential scanning calorimetry, fluorescence spectroscopy, infrared spectroscopy, circular dichroism, patch clamp) and various biological techniques can be used as research methods.

We look forward to receiving your contributions.

Dr. Jadwiga Maniewska
Dr. Żaneta Czyżnikowska
Guest Editors

Manuscript Submission Information

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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. Membranes 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 2700 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

  • drug–membrane interaction
  • flavonoids–membrane interaction
  • bioactive compounds
  • model lipid membranes
  • membrane proteins
  • membrane phospholipid composition
  • membrane channels
  • surfactants
  • new drug targets
  • cancer multidrug resistance
  • cancer therapy
  • cancer chemoprevention

Published Papers (9 papers)

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Research

16 pages, 2100 KiB  
Article
ΔM4: Membrane-Active Peptide with Antitumoral Potential against Human Skin Cancer Cells
by Estefanía Fandiño-Devia, Gloria A. Santa-González, Maria C. Klaiss-Luna, Ibeth Guevara-Lora, Verónica Tamayo and Marcela Manrique-Moreno
Membranes 2023, 13(7), 671; https://doi.org/10.3390/membranes13070671 - 14 Jul 2023
Cited by 2 | Viewed by 1429
Abstract
Peptides have become attractive potential agents due to their affinity to cancer cells. In this work, the biological activity of the peptide ΔM4 against melanoma cancer cell line A375, epidermoid carcinoma cell line A431, and non-tumoral HaCaT cells was evaluated. The cytotoxic MTT [...] Read more.
Peptides have become attractive potential agents due to their affinity to cancer cells. In this work, the biological activity of the peptide ΔM4 against melanoma cancer cell line A375, epidermoid carcinoma cell line A431, and non-tumoral HaCaT cells was evaluated. The cytotoxic MTT assay demonstrates that ΔM4 show five times more activity against cancer than non-cancer cells. The potential membrane effect of ΔM4 was evaluated through lactate dehydrogenase release and Sytox uptake experiments. The results show a higher membrane activity of ΔM4 against A431 in comparison with the A375 cell line at a level of 12.5 µM. The Sytox experiments show that ΔM4 has a direct effect on the permeability of cancer cells in comparison with control cells. Infrared spectroscopy was used to study the affinity of the peptide to membranes resembling the composition of tumoral and non-tumoral cells. The results show that ΔM4 induces a fluidization effect on the tumoral lipid system over 5% molar concentration. Finally, to determine the appearance of phosphatidylserine on the surface of the cell, flow cytometry analyses were performed employing an annexin V–PE conjugate. The results suggest that 12.5 µM of ΔM4 induces phosphatidylserine translocation in A375 and A431 cancer cells. The findings of this study support the potential of ΔM4 as a selective agent for targeting cancer cells. Its mechanism of action demonstrated selectivity, membrane-disrupting effects, and induction of phosphatidylserine translocation. Full article
(This article belongs to the Special Issue Biological Membrane and Bioactive Compounds Interactions)
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15 pages, 2588 KiB  
Article
Interaction of Quercetin, Cyanidin, and Their O-Glucosides with Planar Lipid Models: Implications for Their Biological Effects
by Daniela Meleleo, Pinarosa Avato, Filomena Conforti, Maria Pia Argentieri, Giovanni Messina, Giuseppe Cibelli and Rosanna Mallamaci
Membranes 2023, 13(6), 600; https://doi.org/10.3390/membranes13060600 - 14 Jun 2023
Cited by 3 | Viewed by 1329
Abstract
Flavonoids are specialized metabolites produced by plants, as free aglycones or as glycosylated derivatives, which are particularly endowed with a variety of beneficial health properties. The antioxidant, anti-inflammatory, antimicrobial, anticancer, antifungal, antiviral, anti-Alzheimer’s, anti-obesity, antidiabetic, and antihypertensive effects of flavonoids are now known. [...] Read more.
Flavonoids are specialized metabolites produced by plants, as free aglycones or as glycosylated derivatives, which are particularly endowed with a variety of beneficial health properties. The antioxidant, anti-inflammatory, antimicrobial, anticancer, antifungal, antiviral, anti-Alzheimer’s, anti-obesity, antidiabetic, and antihypertensive effects of flavonoids are now known. These bioactive phytochemicals have been shown to act on different molecular targets in cells including the plasma membrane. Due to their polyhydroxylated structure, lipophilicity, and planar conformation, they can either bind at the bilayer interface or interact with the hydrophobic fatty acid tails of the membrane. The interaction of quercetin, cyanidin, and their O-glucosides with planar lipid membranes (PLMs) similar in composition to those of the intestine was monitored using an electrophysiological approach. The obtained results show that the tested flavonoids interact with PLM and form conductive units. The modality of interaction with the lipids of the bilayer and the alteration of the biophysical parameters of PLMs induced by the tested substances provided information on their location in the membrane, helping to elucidate the mechanism of action which underlies some pharmacological properties of flavonoids. To our knowledge, the interaction of quercetin, cyanidin, and their O-glucosides with PLM surrogates of the intestinal membrane has never been previously monitored. Full article
(This article belongs to the Special Issue Biological Membrane and Bioactive Compounds Interactions)
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15 pages, 2354 KiB  
Article
New Meloxicam Derivatives—Synthesis and Interaction with Phospholipid Bilayers Measured by Differential Scanning Calorimetry and Fluorescence Spectroscopy
by Jadwiga Maniewska, Justyna Gąsiorowska, Żaneta Czyżnikowska, Krystyna Michalak and Berenika M. Szczęśniak-Sięga
Membranes 2023, 13(4), 416; https://doi.org/10.3390/membranes13040416 - 6 Apr 2023
Cited by 1 | Viewed by 1825
Abstract
The purpose of the present paper was to assess the ability of five newly designed and synthesized meloxicam analogues to interact with phospholipid bilayers. Calorimetric and fluorescence spectroscopic measurements revealed that, depending on the details of the chemical structure, the studied compounds penetrated [...] Read more.
The purpose of the present paper was to assess the ability of five newly designed and synthesized meloxicam analogues to interact with phospholipid bilayers. Calorimetric and fluorescence spectroscopic measurements revealed that, depending on the details of the chemical structure, the studied compounds penetrated bilayers and affected mainly their polar/apolar regions, closer to the surface of the model membrane. The influence of meloxicam analogues on the thermotropic properties of DPPC bilayers was clearly visible because these compounds reduced the temperature and cooperativity of the main phospholipid phase transition. Additionally, the studied compounds quenched the fluorescence of prodan to a higher extent than laurdan, what pointed to a more pronounced interaction with membrane segments close to its surface. We presume that a more pronounced intercalation of the studied compounds into the phospholipid bilayer may be related to the presence of the molecule of a two-carbon aliphatic linker with a carbonyl group and fluorine substituent/trifluoromethyl group (compounds PR25 and PR49) or the three-carbon linker together with the trifluoromethyl group (PR50). Moreover, computational investigations of the ADMET properties have shown that the new meloxicam analogues are characterized by beneficial expected physicochemical parameters, so we may presume that they will have a good bioavailability after an oral administration. Full article
(This article belongs to the Special Issue Biological Membrane and Bioactive Compounds Interactions)
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21 pages, 6818 KiB  
Article
Miscibility of Phosphatidylcholines in Bilayers: Effect of Acyl Chain Unsaturation
by Agata Żak, Natan Rajtar, Waldemar Kulig and Mariusz Kepczynski
Membranes 2023, 13(4), 411; https://doi.org/10.3390/membranes13040411 - 5 Apr 2023
Cited by 1 | Viewed by 1491
Abstract
The miscibility of phospholipids in a hydrated bilayer is an issue of fundamental importance for understanding the organization of biological membranes. Despite research on lipid miscibility, its molecular basis remains poorly understood. In this study, all-atom MD simulations complemented by Langmuir monolayer and [...] Read more.
The miscibility of phospholipids in a hydrated bilayer is an issue of fundamental importance for understanding the organization of biological membranes. Despite research on lipid miscibility, its molecular basis remains poorly understood. In this study, all-atom MD simulations complemented by Langmuir monolayer and DSC experiments have been performed to investigate the molecular organization and properties of lipid bilayers composed of phosphatidylcholines with saturated (palmitoyl, DPPC) and unsaturated (oleoyl, DOPC) acyl chains. The experimental results showed that the DOPC/DPPC bilayers are systems exhibiting a very limited miscibility (strongly positive values of excess free energy of mixing) at temperatures below the DPPC phase transition. The excess free energy of mixing is divided into an entropic component, related to the ordering of the acyl chains, and an enthalpic component, resulting from the mainly electrostatic interactions between the headgroups of lipids. MD simulations showed that the electrostatic interactions for lipid like-pairs are much stronger than that for mixed pairs and temperature has only a slight influence on these interactions. On the contrary, the entropic component increases strongly with increasing temperature, due to the freeing of rotation of acyl chains. Therefore, the miscibility of phospholipids with different saturations of acyl chains is an entropy-driven process. Full article
(This article belongs to the Special Issue Biological Membrane and Bioactive Compounds Interactions)
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13 pages, 2069 KiB  
Article
Structural and Functional Characterization of the Newly Designed Antimicrobial Peptide Crabrolin21
by Francesca Cantini, Paola Giannì, Sara Bobone, Cassandra Troiano, Hugo van Ingen, Renato Massoud, Nicoletta Perini, Luciana Migliore, Philippe Savarin, Charles Sanders, Lorenzo Stella and Marco Sette
Membranes 2023, 13(3), 365; https://doi.org/10.3390/membranes13030365 - 22 Mar 2023
Cited by 2 | Viewed by 1689
Abstract
(1) Background: antimicrobial resistance is becoming a dramatic problem for public health, and the design of new antimicrobial agents is an active research area. (2) Methods: based on our previous work, we designed an improved version of the crabrolin peptide and characterized its [...] Read more.
(1) Background: antimicrobial resistance is becoming a dramatic problem for public health, and the design of new antimicrobial agents is an active research area. (2) Methods: based on our previous work, we designed an improved version of the crabrolin peptide and characterized its functional and structural properties with a wide range of techniques. (3) Results: the newly designed peptide, crabrolin21, is much more active than the previous ones and shows specific selectivity towards bacterial cells. (4) Conclusions: crabrolin21 shows interesting properties and deserves further studies. Full article
(This article belongs to the Special Issue Biological Membrane and Bioactive Compounds Interactions)
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16 pages, 3073 KiB  
Article
Pharmacological Characterization of a Recombinant Mitochondrial ROMK2 Potassium Channel Expressed in Bacteria and Reconstituted in Planar Lipid Bilayers
by Milena Krajewska, Adam Szewczyk, Bogusz Kulawiak and Piotr Koprowski
Membranes 2023, 13(3), 360; https://doi.org/10.3390/membranes13030360 - 21 Mar 2023
Viewed by 2002
Abstract
In the inner mitochondrial membrane, several potassium channels that play a role in cell life and death have been identified. One of these channels is the ATP-regulated potassium channel (mitoKATP). The ROMK2 potassium channel is a potential molecular component of the [...] Read more.
In the inner mitochondrial membrane, several potassium channels that play a role in cell life and death have been identified. One of these channels is the ATP-regulated potassium channel (mitoKATP). The ROMK2 potassium channel is a potential molecular component of the mitoKATP channel. The current study aimed to investigate the pharmacological modulation of the activity of the ROMK2 potassium channel expressed in Escherichia coli bacteria. ROMK2 was solubilized in polymer nanodiscs and incorporated in planar lipid bilayers. The impact of known mitoKATP channel modulators on the activity of the ROMK2 was characterized. We found that the ROMK2 channel was activated by the mitoKATP channel opener diazoxide and blocked by mitoKATP inhibitors such as ATP/Mg2+, 5-hydroxydecanoic acid, and antidiabetic sulfonylurea glibenclamide. These results indicate that the ROMK2 potassium protein may be a pore-forming subunit of mitoKATP and that the impact of channel modulators is not related to the presence of accessory proteins. Full article
(This article belongs to the Special Issue Biological Membrane and Bioactive Compounds Interactions)
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36 pages, 6719 KiB  
Article
Interactions of N-Mannich Bases of Pyrrolo[3,4-c]pyrrole with Artificial Models of Cell Membranes and Plasma Proteins, Evaluation of Anti-Inflammatory and Antioxidant Activity
by Łukasz Szczukowski, Jadwiga Maniewska, Benita Wiatrak, Paulina Jawień, Edward Krzyżak, Aleksandra Kotynia, Aleksandra Marciniak, Maciej Janeczek and Aleksandra Redzicka
Membranes 2023, 13(3), 349; https://doi.org/10.3390/membranes13030349 - 17 Mar 2023
Viewed by 1887
Abstract
Despite the widespread and easy access to NSAIDs, effective and safe treatment of various inflammatory disorders is still a serious challenge because of the severe adverse effects distinctive to these drugs. The Mannich base derivatives of pyrrolo[3,4-c]pyrrole are potent, preferential COX-2 [...] Read more.
Despite the widespread and easy access to NSAIDs, effective and safe treatment of various inflammatory disorders is still a serious challenge because of the severe adverse effects distinctive to these drugs. The Mannich base derivatives of pyrrolo[3,4-c]pyrrole are potent, preferential COX-2 inhibitors with a COX-2/COX-1 inhibitory ratio better than meloxicam. Therefore, we chose the six most promising molecules and subjected them to further in-depth research. The current study presents the extensive biological, spectroscopic and in silico evaluation of the activity and physicochemical properties of pyrrolo[3,4-c]pyrrole derivatives. Aware of the advantages of dual COX–LOX inhibition, we investigated the 15-LOX inhibitory activity of these molecules. We also examined their antioxidant effect in several in vitro experiments in a protection and regeneration model. Furthermore, we defined how studied compounds interact with artificial models of cell membranes, which is extremely important for drugs administered orally with an intracellular target. The interactions and binding mode of the derivatives with the most abundant plasma proteins—human serum albumin and alpha-1-acid glycoprotein—are also described. Finally, we used computational techniques to evaluate their pharmacokinetic properties. According to the obtained results, we can state that pyrrolo[3,4-c]pyrrole derivatives are promising anti-inflammatory and antioxidant agents with potentially good membrane permeability. Full article
(This article belongs to the Special Issue Biological Membrane and Bioactive Compounds Interactions)
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32 pages, 1443 KiB  
Article
Erythrocyte Membrane Biophysical Changes Mediated by Pooled Immunoglobulin G and Hematin: Electrokinetic and Lipid Peroxidation Studies
by Virjinia Doltchinkova, Meglena Kitanova, Rumen Nikolov, Angelina Stoyanova-Ivanova, Ognyan Petkov, Yoana Dikova and Victoria Vitkova
Membranes 2023, 13(3), 281; https://doi.org/10.3390/membranes13030281 - 27 Feb 2023
Viewed by 1506
Abstract
Pooled Immunoglobulin G (IgG), hematin and the membrane-disruptive amphipathic peptide melittin have received attention as powerful biomacromolecules for biomedical and pharmacology applications. Their action on surface properties, oxidation status and epifluorescence properties measured in vitro provide useful information about the functional activity of [...] Read more.
Pooled Immunoglobulin G (IgG), hematin and the membrane-disruptive amphipathic peptide melittin have received attention as powerful biomacromolecules for biomedical and pharmacology applications. Their action on surface properties, oxidation status and epifluorescence properties measured in vitro provide useful information about the functional activity of upper biomacromolecules in erythrocytes in vivo. The hemolysis of erythrocyte membranes, as well as changes in hematocrit and the morphology of erythrocytes, was investigated here via fluorescence microscopy using FITC-concanavalin A binding to cells. The effect of melittin on the membrane capacitance and resistance of model lipid bilayers was probed via electrochemical impedance spectroscopy. Lipid bilayer capacitance was higher in the presence of 0.10 g/L melittin compared to that in the control, which is likely related to bilayer thinning and alterations of the dielectric permittivity of melittin-treated membranes. The biomolecule interactions with red blood cells were probed in physiological media in which the surface of erythrocyte membranes was negatively charged. Surface parameters of erythrocytes are reported upon IgG/hematin and IgG/melittin treatment. Pooled IgG in the presence of melittin, preincubated IgG/hematin preparations promoted a significant decrease in the electrokinetic potential of erythrocytes (Rh-positive). A malondialdehyde (MDA) assay revealed a high rate of lipid peroxidation in erythrocytes treated with IgG/hematin or IgG/melittin preparations. This finding might be a result of pooled IgG interactions with the hematin molecule and the subsequent conformational changes in the protein molecule altering the electrokinetic properties of the erythrocyte membrane related to the Rh group type of erythrocytes. The pooled IgG and hematin are reported to have important consequences for the biophysical understanding of the immunopathological mechanisms of inflammatory, autoimmune and antibody-mediated pathological processes. Full article
(This article belongs to the Special Issue Biological Membrane and Bioactive Compounds Interactions)
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18 pages, 11241 KiB  
Article
Molecular Modeling of Cardiac Sodium Channel with Mexiletine
by Boris S. Zhorov
Membranes 2022, 12(12), 1252; https://doi.org/10.3390/membranes12121252 - 10 Dec 2022
Cited by 2 | Viewed by 1320
Abstract
A sodium channel blocker mexiletine (MEX) is used to treat chronic pain, myotonia and some arrhythmias. Mutations in the pore domain (PD) of voltage-gated sodium channels differently affect tonic block (TB) and use-dependent block (UDB) by MEX. Previous studies identified several MEX-sensing residues [...] Read more.
A sodium channel blocker mexiletine (MEX) is used to treat chronic pain, myotonia and some arrhythmias. Mutations in the pore domain (PD) of voltage-gated sodium channels differently affect tonic block (TB) and use-dependent block (UDB) by MEX. Previous studies identified several MEX-sensing residues in the hNav1.5 channel and demonstrated that the channel block by MEX increases with activation of the voltage-sensing domain III (VSDIII), whereas MEX stabilizes the activated state of VSDIII. Structural rationales for these observations are unclear. Here, Monte Carlo (MC) energy minimizations were used to dock MEX and its more potent analog, Thio-Me2, into the hNav1.5 cryo-EM structure with activated VSDs and presumably inactivated PD. Computations yielded two ensembles of ligand binding poses in close contacts with known MEX-sensing residues in helices S6III, S6IV and P1IV. In both ensembles, the ligand NH3 group approached the cation-attractive site between backbone carbonyls at the outer-pore bottom, while the aromatic ring protruded ether into the inner pore (putative UDB pose) or into the III/IV fenestration (putative TB pose). In silico deactivation of VSDIII shifted helices S4–S5III, S5III, S6III and S6IV and tightened the TB site. In a model with activated VSDIII and three resting VSDs, MC-minimized energy profile of MEX pulled from the TB site towards lipids shows a deep local minimum due to interactions with 11 residues in S5III, P1III, S6III and S6IV. The minimum may correspond to an interim binding site for MEX in the hydrophobic path to the TB site along the lipid-exposed sides of repeats III and IV where 15 polar and aromatic residues would attract cationic blockers. The study explains numerous experimental data and suggests the mechanism of allosteric modification of the MEX binding site by VSDIII. Full article
(This article belongs to the Special Issue Biological Membrane and Bioactive Compounds Interactions)
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