SELECTIVE CYTOTOXICITY OF DERMASEPTIN S3 TOWARD INTRAERYTHROCYTIC PLASMODIUM-FALCIPARIUM AND THE UNDERLYING MOLECULAR-BASIS

Citation
Jk. Ghosh et al., SELECTIVE CYTOTOXICITY OF DERMASEPTIN S3 TOWARD INTRAERYTHROCYTIC PLASMODIUM-FALCIPARIUM AND THE UNDERLYING MOLECULAR-BASIS, The Journal of biological chemistry, 272(50), 1997, pp. 31609-31616
Citations number
49
ISSN journal
00219258
Volume
272
Issue
50
Year of publication
1997
Pages
31609 - 31616
Database
ISI
SICI code
0021-9258(1997)272:50<31609:SCODST>2.0.ZU;2-L
Abstract
The antimicrobial activity of various naturally occurring microbicidal peptides was reported to result from their interaction with microbial membrane. In this study, we investigated the cytotoxicity of the hemo lytic peptide dermaseptin S4 (DS4) and the nonhemolytic peptide dermas eptin S3 (DS3) toward human erythrocytes infected by the malaria paras ite Plasmodium falciparum. Both DS4 and DS3 inhibited the parasite's a bility to incorporate [H-3]hypoxanthine. However, while DS4 was toxic toward both the parasite and the host erythrocyte, DS3 was toxic only toward the intraerythrocytic parasite. To gain insight into the mechan ism of this selective cytotoxicity, we labeled the peptides with fluor escent probes and investigated their organization in solution and in m embranes. In Plasmodium-infected cells, rhodamine-labeled peptides int eracted directly with the intracellular parasite, in contrast to nonin fected cells, where the peptides remained bound to the erythrocyte pla sma membrane. Binding experiments to phospholipid membranes revealed t hat DS3 and DS4 had similar binding characteristics. Membrane permeati on studies indicated that the peptides were equally potent in permeati ng phosphatidylserine/phosphatidylcholine vesicles, whereas DS4 was mo re permeative with phosphatidylcholine vesicles. In aqueous solutions, DS4 was found to be in a higher aggregation state. Nevertheless, both DS3 and DS4 spontaneously dissociated to monomers upon interaction wi th vesicles, albeit with different kinetics. In light of these results , we propose a mechanism by which dermaseptins permeate cells and affe ct intraerythrocytic parasites.