A class of potent antimalarials and their specific accumulation in infected erythrocytes

被引:146
作者
Wengelnik, K
Vidal, V
Ancelin, ML
Cathiard, AM
Morgat, JL
Kocken, CH
Calas, M
Herrera, S
Thomas, AW
Vial, HJ
机构
[1] Univ Montpellier 2, CNRS, UMR 5539, F-34095 Montpellier 5, France
[2] Univ Montpellier 2, CNRS, UMR 5810, F-34095 Montpellier, France
[3] Univ Montpellier 1, Fac Pharm, CRBA, CNRS UMR 5473, F-34060 Montpellier, France
[4] Biomed Primate Res Ctr, Dept Parasitol, NL-2280 GH Rijswijk, Netherlands
[5] Univ Valle, Fdn Ctr Primates, Cali, Colombia
关键词
D O I
10.1126/science.1067236
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
During asexual development within erythrocytes, malaria parasites synthesize considerable amounts of membrane. This activity provides an attractive target for chemotherapy because it is absent from mature erythrocytes. We found that compounds that inhibit phosphatidylcholine biosynthesis de novo from choline were potent antimalarial drugs. The lead compound, G25, potently inhibited in vitro growth of the human malaria parasites Plasmodium falciparum and P. vivax and was 1000-fold less toxic to mammalian cell lines. A radioactive derivative specifically accumulated in infected erythrocytes to levels several hundredfold higher than in the surrounding medium, and very low dose G25 therapy completely cured monkeys infected with P. falciparum and A cynomolgi.
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收藏
页码:1311 / 1314
页数:4
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