TY - JOUR
T1 - Direct interaction of dermaseptin S4 aminoheptanoyl derivative with intraerythrocytic malaria parasite leading to increased specific antiparasitic activity in culture
AU - Efron, Leah
AU - Dagan, Arie
AU - Gaidukov, Leonid
AU - Ginsburg, Hagai
AU - Mor, Amram
PY - 2002/7/5
Y1 - 2002/7/5
N2 - Antiplasmodial activity of the dermaseptin S4 derivative K4 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 intra-cellular parasites and support a mechanism whereby NC7-P crosses the host cell plasma membrane and disrupts the parasite membrane(s).
AB - Antiplasmodial activity of the dermaseptin S4 derivative K4 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 intra-cellular parasites and support a mechanism whereby NC7-P crosses the host cell plasma membrane and disrupts the parasite membrane(s).
UR - http://www.scopus.com/inward/record.url?scp=0037025297&partnerID=8YFLogxK
U2 - 10.1074/jbc.M202089200
DO - 10.1074/jbc.M202089200
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 11937508
AN - SCOPUS:0037025297
SN - 0021-9258
VL - 277
SP - 24067
EP - 24072
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 27
ER -