ANTIMALARIAL EFFECTS OF PEPTIDE INHIBITORS OF A PLASMODIUM-FALCIPARUM CYSTEINE PROTEINASE

被引:173
作者
ROSENTHAL, PJ
WOLLISH, WS
PALMER, JT
RASNICK, D
机构
[1] SAN FRANCISCO GEN HOSP, DEPT MED, SAN FRANCISCO, CA 94110 USA
[2] PROTOTEK INC, DUBLIN, CA 94568 USA
关键词
CHEMOTHERAPY; HEMOGLOBIN; MALARIA; PROTEASE; PROTEINASE INHIBITOR;
D O I
10.1172/JCI115456
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
We previously identified a Plasmodium falciparum trophozoite cysteine proteinase (TCP) and hypothesized that it is required for the degradation of host hemoglobin by intraerythrocytic malaria parasites. To test this hypothesis and to evaluate TCP as a chemotherapeutic target, we examined the antimalarial effects of a panel of peptide fluoromethyl ketone proteinase inhibitors. For each inhibitor, effectiveness at inhibiting the activity of TCP correlated with effectiveness at both blocking hemoglobin degradation and killing cultured parasites. Benzyloxycarbonyl (Z)-Phe-Arg-CH2F, the most potent inhibitor, inhibited TCP at picomolar concentrations and blocked hemoglobin degradation and killed parasites at nanomolar concentrations. Micromolar concentrations of the inhibitor were nontoxic to cultured mammalian cells. These results support the hypothesis that TCP is a necessary hemoglobinase and suggest that it is a promising chemotherapeutic target.
引用
收藏
页码:1467 / 1472
页数:6
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