Abstract
Cyclosporin A (CsA), a hydrophobic cyclic peptide produced by the fungus Tolypocladium inflatum, is well known for its high efficiency as an immunosuppressor for transplanted organs and anti-inflammatory properties; however, it is also active as antiparasitic (antimalarial) drug. Antimalarial mechanism of CsA action lacks a detailed understanding at molecular level. Due to a high lipophilicity of CsA, it is able to interact with lipids of cellular membrane; however, molecular targets of this drug are still unknown. To get a deeper insight into the mode of antimalarial activity of CsA, it is of utmost importance to examine its interactions with membrane components. To reach this goal, the Langmuir monolayer technique, which serves as a very useful, easy to handle and controllable model of biomembranes, has been employed. In this work, the interactions between CsA and main membrane lipids, i.e., cholesterol (Chol), 2-oleoyl-1-palmitoyl-3-phosphocholine (POPC), and sphingomyelin (SM), have been investigated. Attractive interactions are observed only for CsA mixtures with SM, while repulsive forces occur in systems containing remaining membrane lipids. Taking into consideration mutual interactions between membrane lipids (Chol–SM; Chol–POPC and SM–POPC), the behavior of CsA in model erythrocyte membrane of normal and infected cells has been analyzed. Our results prove strong affinity of CsA to SM in membrane environment. Since normal and parasitized erythrocytes differ significantly in the level of SM, this phospholipid may be considered as a molecular target for antimalarial activity of CsA.Electronic supplementary materialThe online version of this article (doi:10.1007/s00232-015-9814-9) contains supplementary material, which is available to authorized users.
Highlights
Cyclosporin A (CsA), a hydrophobic cyclic peptide produced by the fungus Tolypocladium inflatum, is well known for its high efficiency as an immunosuppressor for transplanted organs and anti-inflammatory properties; it is active as antiparasitic drug
Cyclosporin A (CsA) is a hydrophobic cyclic peptide produced by soil fungus Tolypocladium inflatum and composed of 11 amino acids, mostly methylated, that are linked by several hydrogen bonds (Fig. 1) (Borel et al 1979; Czogalla 2009)
Cholesterol was found to decrease penetration of CsA into DPPC bilayer in a pressure-dependent way (Soderlund et al 1999). These results unambiguously prove membrane activity of CsA and suggest that modified upon infection, erythrocyte membrane may be a key factor for the antiparasitic property of this peptide
Summary
Cyclosporin A (CsA) is a hydrophobic cyclic peptide produced by soil fungus Tolypocladium inflatum and composed of 11 amino acids, mostly methylated, that are linked by several hydrogen bonds (Fig. 1) (Borel et al 1979; Czogalla 2009). Parasitized erythrocytes undergo substantial modifications in structure (shape deformation (Holz 1977)) and function—most important alterations include modified transport (Cabantchik 1989), lower exchange rate of cholesterol as well as marked increase in membrane permeability, and fluidity (Hsiao et al 1991; Maguire and Sherman 1990 and references therein) These changes occur in consequence of a different composition of infected red blood cells (IRBC) as compared to normal ones (NRBC) as reported in many papers (specified in Maguire and Sherman 1990 for infections with Plasmodium falciparum). To find out how different lipid composition modulates the interaction of CsA, we have modeled erythrocyte membrane of normal and infected cells and studied the effect exerted by the addition of CsA using the Langmuir monolayer technique (Gaines 1966). Following data, presented in (Shalmiev and Ginsburg 1993, Table 1) for SM:PC ratio for erythrocytes infected with various strains of P. falciparum, is 0.2 on average
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