title: 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).
authors.affiliation: Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram 91904 Jerusalem, Israel.
authors.forename: Leah
authors.initials: L
authors.lastname: Efron
authors.forename: Arie
authors.initials: A
authors.lastname: Dagan
authors.forename: Leonid
authors.initials: L
authors.lastname: Gaidukov
authors.forename: Hagai
authors.initials: H
authors.lastname: Ginsburg
authors.forename: Amram
authors.initials: A
authors.lastname: Mor
mesh_terms: D000595:Amino Acid Sequence; D029845:Amphibian Proteins; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D029845:Amphibian Proteins; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; C109653:dermaseptin 4 protein, Phyllomedusa