Irreversible inhibition of S-adenosylmethionine decarboxylase in Plasmodium falciparum-infected erythrocytes: growth inhibition in vitro.
Blocking spermidine and spermine synthesis in Plasmodium falciparum-infected erythrocytes with irreversible inhibitors of S-adenosylmethionine decarboxylase (AdoMet DC; EC 4.1.1.50), prevented the growth of the parasite in vitro. The most potent of these compounds, MDL 73811, inhibited growth of chloroquine-sensitive and -resistant strains of P. falciparum equally, with an IC50 of 2-3 microM. Other structurally related compounds also inhibited parasite proliferation, but to a lesser degree, determined apparently by their potency for inhibition of AdoMet DC. The growth inhibition by MDL 73811 could be alleviated by incubating infected erythrocytes with spermidine and spermine, but not putrescine. Parasites treated with the drug were arrested at the trophozoite stage of the erythrocytic cycle and had putrescine levels which were elevated by about 3- to 4-fold. Treatment of crude extracts of purified parasites with 1 microM MDL 73811 inhibited AdoMet DC activity by greater than 90%. These biochemical changes in P. falciparum-infected cells were consistent with AdoMet DC inhibition being the primary effect of MDL 73811 treatment.
Wright
P S
PS
Marion Merrell Dow Research Institute, Cincinnati, OH 45215-6300.
Byers
T L
TL
Cross-Doersen
D E
DE
McCann
P P
PP
Bitonti
A J
AJ
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology*; D000518:Eflornithine / Q000494:pharmacology; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D011073:Polyamines / Q000032:analysis; D013095:Spermidine / Q000494:pharmacology; D013096:Spermine / Q000494:pharmacology
D003839:Deoxyadenosines; D011073:Polyamines; D013096:Spermine; C065859:MDL 73811; D002738:Chloroquine; D012437:Adenosylmethionine Decarboxylase; D013095:Spermidine; D000518:Eflornithine