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.