The Potent Antimalarial Peptide Cyclosporin A Induces the Aggregation and Permeabilization of Sphingomyelin-Rich Membranes

Abstract

Cyclosporin A (CsA) is a hydrophobic peptide drug produced by the fungus Tolypocladium inflatum. CsA is commonly used as an immunosuppressive drug, but it also has antimalarial activity. The immunosuppressive activity of CsA is clearly due to its association with specific proteins of immune cells such as cyclophilins. By contrast, the antimalarial properties of this peptide are completely independent of the association with a parasite's cyclophilins. Because of its hydrophobicity, CsA may interact with biological membranes, which may participate in its therapeutic effect. Recently, we have shown a marked preference of CsA for insertion into sphingomyelin (SM) monolayers. In this article, we measure for the first time the ability of CsA to induce permeabilization and aggregation and to change the lipid order, especially in the presence of SM. Calcein-release experiments permitted us to show that CsA causes the leakage of the fluorescent probe from SM-rich liposomes by 40% and PC liposomes by 11%, suggesting a lipid-selective effect. Electron microscopy and dynamic light scattering experiments confirmed the different interaction of CsA with SM and PC vesicles: it formed much larger aggregates with SM than with PC. Our results taken together suggest that CsA could specifically weaken and aggregate SM-rich membranes, which could in turn explain why CsA is efficient in the treatment of malaria. Indeed, CsA could inhibit the development of Plasmodium by permeabilizing and aggregating the SM-rich membrane network formed by the parasite during its intraerythrocytic growth cycle.

The Antiviral Properties of Cyclosporine. Focus on Coronavirus, Hepatitis C Virus, Influenza Virus, and Human Immunodeficiency Virus Infections

“…A study conducted in 2011 provided the preliminary explanation of how cyclosporine might inhibit the development of Plasmodium. The antimalarial activity of cyclosporine might be explained by the phenomenon of the permeabilization and aggregation of the sphingomyelin-rich membrane network produced by the parasites during their development in erythrocytes [64].…”

Cyclosporin A in Membrane Lipids Environment: Implications for Antimalarial Activity of the Drug—The Langmuir Monolayer Studies

“…Namely, the mode of action of quinoline antimalarials is based on their accumulation in parasites vacuole and inhibition of the polymerization of heme (produced by parasites from hemoglobin digestion), which is toxic to the parasites in the free form (Sherman 1979 ). CsA does not interfere with heme polymerization (Azouzi et al 2011 ), and therefore, its antimalarial activity must be based on a different mechanism. Many studies using liposomes as membrane models (reviewed in Czogalla 2009 ) have proved that CsA incorporates and interacts with lipid membranes.…”

Cyclosporine A Treatment Abrogates Ischemia‐Induced Neuronal Cell Death by Preserving Mitochondrial Integrity through Upregulation of the Parkinson's Disease‐Associated Protein DJ‐1

“…CsA is a hydrophobic peptide drug, with its immunosuppressive activity closely associated with its binding to specific proteins of immune cells, such as CypD. Because of its hydrophobicity, CsA may interact with biological membranes, which may mediate its therapeutic effect . DJ‐1 protein stability and dimerization have been shown to be disrupted across the entire dimer interface, characterized by extended hydrophobic surfaces involved in dimer formation .…”