Antimalarial activities of dermaseptin S4 derivatives

The hemolytic antimicrobial peptide dermaseptin S4 was recently shown to ex ert antimalarial activity. In this study, we attempted to understand the un derlying mechanism(s) and identify derivatives with improved antimalarial a ctivity. A number of dermaseptin S4 derivatives inhibited parasite growth w ith a 50% inhibitory concentration (IC50) in the micromolar range. Among th ese, the substituted S4 analog K4K20-S4 was the most potent (IC50 = 0.2 mu M), while its shorter version, K-4-S4(1-13)a, retained a considerable poten cy (IC50 = 6 mu M) Both K4K20-S4 and K-4-S4(1-13)a inhibited growth of the parasites more at the trophozoite stage than at the ring stage. Significant growth inhibition was observed after as little as 1 min of exposure to pep tides and proceeded with nearly linear kinetics. The peptides selectively l ysed infected red blood cells (RBC) while having a weaker effect on noninfe cted RBC. Thus, K4K20-S4 lysed trophozoites at concentrations similar to th ose that inhibited their proliferation, but trophozoites were >30-fold more susceptible than normal RBC to the lytic effect of K4K20-S4, the most hemo lytic dermaseptin. The same trend was observed with K-4-S4(1-13)a. The D is omers of K4K20-S4 or K-4-S4(1-13)a were as active as the L counterparts, in dicating that antimalarial activity of these peptides, like their membrane- lytic activity, is not mediated by specific interactions with a chiral cent er. Moreover, dissipation of transmembrane potential experiments with infec ted cells indicated that the peptides induce damage in the parasite's plasm a membrane. Fluorescence confocal microscopy analysis of treated infected c ells also indicated that the peptide is able to find its way through the co mplex series of membranes and interact directly with the intracellular para site. Overall, the data showed that dermaseptins exert antimalarial activit y by lysis of infected cells. Dermaseptin derivatives are also able to disr upt the parasite plasma membrane without harming that of the host RBC.