The Degree of Hydroxylation of Phenolic Rings Determines the Ability of Flavonoids and Stilbenes to Inhibit Calcium-Mediated Membrane Fusion

Abstract

This paper discusses the possibility of using plant polyphenols as viral fusion inhibitors with a lipid-mediated mechanism of action. The studied agents are promising candidates for the role of antiviral compounds due to their high lipophilicity, low toxicity, bioavailability, and relative cheapness. Fluorimetry of calcein release at the calcium-mediated fusion of liposomes, composed of a ternary mixture of dioleoyl phosphatidylcholine, dioleoyl phosphatidylglycerol, and cholesterol, in the presence of 4′-hydroxychalcone, cardamonin, isoliquiritigenin, phloretin, resveratrol, piceatannol, daidzein, biochanin A, genistein, genistin, liquiritigenin, naringenin, catechin, taxifolin, and honokiol, was performed. It was found that piceatannol significantly inhibited the calcium-induced fusion of negatively charged vesicles, while taxifolin and catechin showed medium and low antifusogenic activity, respectively. As a rule, polyphenols containing at least two OH-groups in both phenolic rings were able to inhibit the calcium-mediated fusion of liposomes. In addition, there was a correlation between the ability of the tested compounds to inhibit vesicle fusions and to perturb lipid packing. We suggest that the antifusogenic action of polyphenols was determined by the depth of immersion and the orientation of the molecules in the membrane.

Modulation of the Dipole Potential of Model Lipid Membranes with Phytochemicals: Molecular Mechanisms, Structure–Activity Relationships, and Implications in Reconstituted Ion Channels

“…The latter may be due to the relatively high dipole moments of their molecules, which can be oriented opposite to the existing total dipole moment of the membrane-forming lipids and water sorbed on the surface of the bilayer, and may be due to a decrease in the packing density of the lipids (i.e., a decrease in the surface density of the dipoles, n). The latter assumption is confirmed by a decrease in the melting temperature of saturated phosphocholines of more than 1 • C upon the incorporation of phloretin, 4-hydroxychalcone, butein, cardamonin, isoliquiritigenin, naringenin, licochalcone A, biochanin A, piperine, capsaicin, and dihydrocapsaicin [117,125,128]. The exceptions are highly hydroxylated flavonols, such as quercetin and myricetin, which significantly reduce the dipole potential of the membrane (Table 1) but do not practically affect the packing density of the lipids in the membrane [129].…”

Echinocandins have an alternative mode of action on biomimetic membranes that is not directly related to the functioning of (1,3) beta-glucan synthase

“…Taking into account that molecules of MCF possess negative net charge, the increase in the number of MCF channels at the phloretin introduction was not a result of reduction of bilayer dipole potential. Considering that phloretin also decrease a lipid packing stress in the membrane 44 , we proposed that the increase in the number of MCF channels was due to a perturbation in the elastic properties of the membrane.…”