title: In vitro antiplasmodium effects of dermaseptin S4 derivatives.
abstract: The 13-residue dermaseptin S4 derivative K(4)S4(1-13)a (P) was previously shown to kill intraerythrocytic malaria parasites through the lysis of the host cells. In this study, we have sought peptides that will kill the parasite without lysing the erythrocyte. To produce such peptides, 26 compounds of variable structure and size were attached to the N terminus of P and screened for antiplasmodium and hemolytic activities in cultures of Plasmodium falciparum. Results from this screen indicated that increased hydrophobicity results in amplified antiplasmodium effect, irrespective of the linearity or bulkiness of the additive. However, increased hydrophobicity also was generally associated with increased hemolysis, with the exception of two derivatives: propionyl-P (C3-P) and isobutyryl-P (iC4-P). Both acyl-peptides were more effective than P, with 50% growth inhibition at 3.8, 4.3, and 7.7 microM, respectively. The antiparasitic effect was time dependent and totally irreversible, implying a cytotoxic effect. The peptides were also investigated in parallel for their ability to inhibit parasite growth and to induce hemolysis in infected and uninfected erythrocytes. Whereas the dose dependence of growth inhibition and hemolysis of infected cells overlapped when cells were treated with P, the acyl-peptides exerted 50% growth inhibition at concentrations that did not cause hemolysis. Noticeably, the acyl derivatives, but not P, were able to dissipate the parasite plasma membrane potential and cause depletion of intraparasite potassium under nonhemolytic conditions. These results clearly demonstrate that the acyl-peptides can affect parasite viability in a manner that is dissociated from lysis of the host cell. Overall, the data indicate the potential usefulness of this strategy for development of selective peptides as investigative tools and eventually as antimalarial agents.
authors.affiliation: Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram 91904, Jerusalem, Israel.
authors.forename: Arie
authors.initials: A
authors.lastname: Dagan
authors.forename: Leah
authors.initials: L
authors.lastname: Efron
authors.forename: Leonid
authors.initials: L
authors.lastname: Gaidukov
authors.forename: Amram
authors.initials: A
authors.lastname: Mor
authors.forename: Hagai
authors.initials: H
authors.lastname: Ginsburg
mesh_terms: D029845:Amphibian Proteins; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D019151:Peptide Library; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D011188:Potassium / Q000097:blood / Q000378:metabolism
chemical_list: D029845:Amphibian Proteins; D000962:Antimalarials; D023181:Antimicrobial Cationic Peptides; D019151:Peptide Library; C109653:dermaseptin 4 protein, Phyllomedusa; D011188:Potassium