In vitro cytocidal effect of novel lytic peptides on
 Plasmodium falciparum
 and
 Trypanosoma cruzi
 1

Jaynes, Jesse M.; Burton, Catherine A.; Barr, Stephen B.; Jeffers, Gale W.; Julian, Gordon R.; White, Kenneth L.; Enright, Frederick M.; Klei, Thomas R.; Laine, Roger A.

doi:10.1096/fasebj.2.13.3049204

Cited by 94 publications

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“…This was a natural extension of our earlier work on cecropin analogs with single residue substitutions [ 11,121, on cecropin model peptides [ 131, and on a hybrid between cecropins A and D [ 141 with an improved ability to form ion channels [15]. Two analogs of cecropin B have been reported to inhibit the blood stream forms of the malaria parasite [16], and recently magainin 2 and cecropin B were found to inhibit the mosquito forms of the parasite [17]. We have therefore also tested our most potent hybrid peptide for ability to inhibit the growth of the blood stream forms of the malaria parasite.…”

Section: Introductionmentioning

confidence: 72%

Antibacterial and antimalarial properties of peptides that are cecropin‐melittin hybrids

et al. 1989

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Solid phase synthesis was used to produce 5 hybrid peptides containing sequences from the antibacterial peptide, cecropin A, and from the bee venom toxin, melittin. Four of these chimeric peptides showed good antibacterial activity against representative Gram-negative and Gram-positive bacterial species. The best hybrid, cecropin A(l-13)-melittin(l-13) was IOO-fold more active than cecropin A against Staphylococcus uureus. It was also a lo-fold better antimalarial agent than cecropin B or magainin 2. Sheep red cells were lysed by melittin at low concentrations, but not by the hybrid molecules, even at 50 times higher concentrations.Cecropin A; Melittin; (Staphylococcus aureus, Plasmodium falciparium)

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Section: Introductionmentioning

confidence: 72%

Antibacterial and antimalarial properties of peptides that are cecropin‐melittin hybrids

et al. 1989

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“…This devastating situation stems from the ever-increasing resistance of parasites to available drugs, and new chemotherapeutic means have to be developed. Recently, various animal-derived peptide-based antimicrobials have emerged as interesting tools for exploring new potential antiplasmodiams agents (8,12,13).…”

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confidence: 99%

In Vitro Antiplasmodium Effects of Dermaseptin S4 Derivatives

Dagan

Efron

Gaidukov

et al. 2002

Antimicrob Agents Chemother

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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 M, 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.

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“…Antimicrobial peptides have recently emerged as interesting tools for exploring new antimalarial targets (2)(3)(4)(5)(6). These ubiquitous peptides vary considerably in structure, size, amino acid sequence, and spectrum of action (7)(8)(9)(10)(11), but the most potent peptides always have a pronounced amphipathic and distinctly basic character (12)(13)(14)(15)(16).…”

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confidence: 99%

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

Efron

Dagan

Gaidukov

et al. 2002

Journal of Biological Chemistry

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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).

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In vitro cytocidal effect of novel lytic peptides on Plasmodium falciparum and Trypanosoma cruzi ¹

Cited by 94 publications

References 0 publications

Antibacterial and antimalarial properties of peptides that are cecropin‐melittin hybrids

Antibacterial and antimalarial properties of peptides that are cecropin‐melittin hybrids

In Vitro Antiplasmodium Effects of Dermaseptin S4 Derivatives

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

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In vitro cytocidal effect of novel lytic peptides on Plasmodium falciparum and Trypanosoma cruzi 1

Cited by 94 publications

References 0 publications

Antibacterial and antimalarial properties of peptides that are cecropin‐melittin hybrids

Antibacterial and antimalarial properties of peptides that are cecropin‐melittin hybrids

In Vitro Antiplasmodium Effects of Dermaseptin S4 Derivatives

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

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In vitro cytocidal effect of novel lytic peptides on Plasmodium falciparum and Trypanosoma cruzi ¹