Alkaloids Modulate the Functioning of Ion Channels Produced by Antimicrobial Agents via an Influence on the Lipid Host

Efimova, Svetlana S.; Zakharova, Anastasiia A.; Ostroumova, Olga S.

doi:10.3389/fcell.2020.00537

Cited by 21 publications

(27 citation statements)

References 83 publications

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“…In particular, alkaloids affect the lipid packing [63,64], change lipid phase transition temperatures [65,66], etc. Recently, we performed a detailed study of alkaloid effects on the physical properties of the POPC membrane [67]. To understand the relationship between the alkaloid effects on the fusion and modulation of lipid matrix under their action, the influence of tested alkaloids on the properties of PG and CHOL-enriched bilayers were performed.…”

Section: The Influence Of Alkaloids On the Physical Properties Of The Model Lipid Membranementioning

confidence: 99%

Plant Alkaloids Inhibit Membrane Fusion Mediated by Calcium and Fragments of MERS-CoV and SARS-CoV/SARS-CoV-2 Fusion Peptides

et al. 2021

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To rationalize the antiviral actions of plant alkaloids, the ability of 20 compounds to inhibit calcium-mediated fusion of lipid vesicles composed of phosphatidylglycerol and cholesterol was investigated using the calcein release assay and dynamic light scattering. Piperine, tabersonine, hordenine, lupinine, quinine, and 3-isobutyl-1-methylxanthine demonstrated the most potent effects (inhibition index greater than 50%). The introduction of phosphatidylcholine into the phosphatidylglycerol/cholesterol mixture led to significant changes in quinine, hordenine, and 3-isobutyl-1-methylxanthine efficiency. Comparison of the fusion inhibitory ability of the tested alkaloids, and the results of the measurements of alkaloid-induced alterations in the physical properties of model membranes indicated a potent relationship between a decrease in the cooperativity of the phase transition of lipids and the ability of alkaloids to prevent calcium-mediated vesicle fusion. In order to use this knowledge to combat the novel coronavirus pandemic, the ability of the most effective compounds to suppress membrane fusion induced by fragments of MERS-CoV and SARS-CoV/SARS-CoV-2 fusion peptides was studied using the calcein release assay and confocal fluorescence microscopy. Piperine was shown to inhibit vesicle fusion mediated by both coronavirus peptides. Moreover, piperine was shown to significantly reduce the titer of SARS-CoV2 progeny in vitro in Vero cells when used in non-toxic concentrations.

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Section: The Influence Of Alkaloids On the Physical Properties Of The Model Lipid Membranementioning

confidence: 99%

Plant Alkaloids Inhibit Membrane Fusion Mediated by Calcium and Fragments of MERS-CoV and SARS-CoV/SARS-CoV-2 Fusion Peptides

et al. 2021

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“…It was found that all tested sapogenins (diosgenin, solasodine, uvaol, lupeol, and betulin) did not affect the electrical properties of model lipid membranes (the maximum change in the boundary potential did not exceed 6 mV) ( Figure 2 a, Table 1 ). Obtained K -values are in the range from 6 to 17 μM ( Table S1 Supplementary material ) indicating that saponins can reduce the boundary potential of phosphatidylcholine bilayers at the concentrations higher than plant flavonoids and lower than some alkaloids [ 18 , 19 , 20 , 21 ]. The dissociation constant K calculated from the φ b -changes describes only the electrical aspects of adsorption of the saponins to lipid membranes and does not take into account the adsorption, which does not lead to a change in the transmembrane distribution of the electrical potential.…”

Section: Resultsmentioning

confidence: 99%

“…To verify this possibility, we used ion channels formed by an antimicrobial peptide, gramicidin A (GrA), which is known to be sensitive to alterations in the transmembrane distribution of electrical potentials. According to the literature data [ 21 , 27 ], flavonoid phloretin and alkaloid dihydrocapsaicin, known to decrease the membrane dipole potential, led to an increase in the amplitude and lifetime of cation selective GrA channels.…”

Section: Resultsmentioning

confidence: 99%

Is the Membrane Lipid Matrix a Key Target for Action of Pharmacologically Active Plant Saponins?

Efimova

Ostroumova

2021

IJMS

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This study was focused on the molecular mechanisms of action of saponins and related compounds (sapogenins and alkaloids) on model lipid membranes. Steroids and triterpenes were tested. A systematic analysis of the effects of these chemicals on the physicochemical properties of the lipid bilayers and on the formation and functionality of the reconstituted ion channels induced by antimicrobial agents was performed. It was found that digitonin, tribulosin, and dioscin substantially reduced the boundary potential of the phosphatidylcholine membranes. We concluded that saponins might affect the membrane boundary potential by restructuring the membrane hydration layer. Moreover, an increase in the conductance and lifetime of gramicidin A channels in the presence of tribulosin was due to an alteration in the membrane dipole potential. Differential scanning microcalorimetry data indicated the key role of the sapogenin core structure (steroid or triterpenic) in affecting lipid melting and disordering. We showed that an alteration in pore forming activity of syringomycin E by dioscin might be due to amendments in the lipid packing. We also found that the ability of saponins to disengage the fluorescent marker calcein from lipid vesicles might be also determined by their ability to induce a positive curvature stress.

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“…A further increase in the concentration of the tested agents does not lead to changes in ϕ b . Previously, Ostroumova et al [31,32,35,36] showed that the adsorption of plant polyphenols and alkaloids on model lipid membranes is satisfactorily described by the Langmuir adsorption isotherm with the characteristic parameters: the maximum changes in the boundary potential of bilayers at an infinitely high concentration of the agent (−∆ϕ b (max)) and its desorption constant (K). The linearity of the dependence of ∆ϕ b (max)/∆ϕ b (C) on 1/C (Figure 1b) demonstrated the applicability of the Langmuir adsorption isotherm to the description of the adsorption of the PDE-5 inhibitors on the phospholipid bilayers.…”

Section: The Effects Of Pde-5 Inhibitors On the Electrical Properties Of Lipid Bilayers And Voltage-sensitive Ion Channelsmentioning

confidence: 99%

“…It is known that the single-length pores formed by the polyene macrolide antifungal antibiotic nystatin (Nys) have a lipid mouth of a positive curvature in the opposite direction to the monolayer leaflet. Low-molecular-weight membrane modifiers that induce positive curvature stress enhance the pore-forming ability of Nys [36,56]. Figure 4 demonstrates the effects of 100 µM of PDE-5 inhibitors on the steady-state multichannel activity of Nys in POPC/Chol membranes bathed in 2.0 M KCl, pH 7.4.…”

Section: The Effect Of Pde-5 Inhibitors On the Lipid Packing And Ion Channels Sensitive To Membrane Curvature Stressmentioning

confidence: 99%

Phosphodiesterase Type 5 Inhibitors Greatly Affect Physicochemical Properties of Model Lipid Membranes

2021

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Although phosphodiesterase type 5 inhibitors are widely used and well-studied drugs, the potential benefits of their application in the treatment of various diseases and new drug delivery systems, including liposome forms, are still being discussed. In this regard, the role of the lipid matrix of cell membranes in the pharmacological action of the inhibitors is of special interest. It was shown that sildenafil, vardenafil, and tadalafil caused a significant decrease in the boundary potential of model membranes composed of palmitoyloleoylphosphatidylcholine or its mixture with cholesterol, by 70–80 mV. The reduction in the membrane dipole potential induced by inhibitors led to a 20–25% increase in the conductance of cation-selective pores formed by the antimicrobial peptide gramicidin A. The addition of sildenafil or vardenafil also led to a significant decrease in the temperature of the main phase transition of dipalmytoylphosphatidylcholine, by about 1.5 °C, while tadalafil did not change the melting temperature. Sildenafil, vardenafil, and tadalafil enhanced the pore-forming activity of the antifungal polyene antibiotic nystatin by 11, 13, and 2 times, respectively. This fact might indicate the induction of membrane curvature stress by the inhibitors. The data obtained might be of special interest for the development of lipid-mediated forms of drugs.

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Alkaloids Modulate the Functioning of Ion Channels Produced by Antimicrobial Agents via an Influence on the Lipid Host

Cited by 21 publications

References 83 publications

Plant Alkaloids Inhibit Membrane Fusion Mediated by Calcium and Fragments of MERS-CoV and SARS-CoV/SARS-CoV-2 Fusion Peptides

Plant Alkaloids Inhibit Membrane Fusion Mediated by Calcium and Fragments of MERS-CoV and SARS-CoV/SARS-CoV-2 Fusion Peptides

Is the Membrane Lipid Matrix a Key Target for Action of Pharmacologically Active Plant Saponins?

Phosphodiesterase Type 5 Inhibitors Greatly Affect Physicochemical Properties of Model Lipid Membranes

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