Direct Interaction of Dermaseptin S4 Aminoheptanoyl Derivative with Intraerythrocytic Malaria Parasite Leading to Increased Specific Antiparasitic Activity in Culture

Abstract

Antiplasmodial activity of the dermaseptin S4 derivative K 4 S4(1-13) (P) was shown to be mediated by lysis of the host cells. To identify antiplasmodial peptides with enhanced selectivity, we produced and screened new derivatives based on P and singled out the aminoheptanoylated peptide (NC7-P) for its improved antiplasmodial properties. Compared with P, NC7-P displayed both increased antiparasitic efficiency and reduced hemolysis, including against infected cells. Antiplasmodial activity of P and its derivative was time-dependent and irreversible, implying a cytotoxic effect. But, whereas the dose dependence of growth inhibition and hemolysis of infected cells overlapped when treated with P, NC7-P exerted more than 50% growth inhibition at peptide concentrations that did not cause hemolysis. Noticeably, NC7-P but not P, dissipated the parasite plasma membrane potential and caused depletion of intraparasite potassium at nonhemolytic conditions. Confocal microscopy analysis of infected cells localized the rhodaminated derivative in association with parasite membranes and intraerythrocytic tubulovesicular structures, whereas in normal cells, the peptide localized exclusively at the plasma membrane. Overall, the data demonstrate that antimicrobial peptides can be engineered to act specifically on the membrane of intracellular parasites and support a mechanism whereby NC7-P crosses the host cell plasma membrane and disrupts the parasite membrane(s).

Antimicrobial Peptides from Amphibian Skin Potently Inhibit Human Immunodeficiency Virus Infection and Transfer of Virus from Dendritic Cells to T Cells

“…These net positively charged regions bind to the negatively charged head groups of bacterial membranes (35). Interestingly, A-AMPs possess activity against a variety of microbes, including bacteria (44), fungi (20,(46)(47)(48)(49), viruses (5,16,17,67), and malaria parasites (24).…”

Dermaseptins from Phyllomedusa oreades andPhyllomedusa distincta

“…Indeed, chemically modified dermaseptins have already been shown to effectively lyse the intra-erythrocytic form of Plasmodium falciparum, leaving the host cell unharmed (30). However, there is still a long way before dermaseptins can be considered as an actual and efficient therapy against protozoa infections since their interactions with mammalian blood cells are still poorly investigated.…”

Antibacterial Properties of Dermaseptin S4 Derivatives under Extreme Incubation Conditions

“…Many are active towards a wide range of microorganisms by a mode of action which is still not fully understood but is assumed to involve interaction with the bacterial membrane and its disruption. AMPs do not require interaction with a chiral center for activity, supporting a lower probability for microorganisms to develop efficient resistance mechanisms compared with conventional antibiotics (22,38).AMPs from the dermaseptin family were recently proposed as model peptides for investigating the effects of acyl conjugation (13,17,44). These amphibian-derived AMPs (35, 36) have been amply investigated during the past decade and shown to exert rapid cytolytic activity against a wide range of microorganisms, including gram-negative and gram-positive bacteria, protozoa, filamentous fungi (14,26,35,36), spores of pathogenic bacteria (29), yeasts (11), and intracellular parasites (13,17,30), as well as antiviral activity (5).…”

“…These amphibian-derived AMPs (35, 36) have been amply investigated during the past decade and shown to exert rapid cytolytic activity against a wide range of microorganisms, including gram-negative and gram-positive bacteria, protozoa, filamentous fungi (14,26,35,36), spores of pathogenic bacteria (29), yeasts (11), and intracellular parasites (13,17,30), as well as antiviral activity (5).…”