Asawamahasakda W, Ittarat I, Pu Y M, Ziffer H, Meshnick S R
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor 48109.
Antimicrob Agents Chemother. 1994 Aug;38(8):1854-8. doi: 10.1128/AAC.38.8.1854.
The endoperoxides are a new class of antimalarial agents, of which artemisinin (qinghaosu) is the prototype. We have previously shown that artemisinin is capable of alkylating proteins in model reactions. In the present study, we showed that when Plasmodium falciparum-infected erythrocytes are treated with a radiolabeled antimalarial endoperoxide, either arteether, dihydroartemisinin, or Ro 42-1611 (arteflene), the radioactivity is largely coverted into a form which can be extracted with sodium dodecyl sulfate (SDS). Autoradiograms of SDS-polyacrylamide gels showed that six malarial proteins are radioactively labeled by the three endoperoxides. This labeling occurs at physiological concentrations of drug and is not stage nor strain specific. The labeled proteins were not the most abundant proteins seen on Coomassie-stained gels. No proteins were labeled when uninfected erythrocytes were treated with these drugs, nor when infected erythrocytes were treated with the inactive analog deoxyarteether. Thus, the antimalarial endoperoxides appear to react with specific malarial proteins.
内过氧化物是一类新型抗疟药，其中青蒿素（青蒿素）是原型。我们之前已经表明，青蒿素能够在模型反应中使蛋白质烷基化。在本研究中，我们发现，当用放射性标记的抗疟内过氧化物（蒿甲醚、双氢青蒿素或Ro 42-1611（蒿乙醚））处理恶性疟原虫感染的红细胞时，放射性大部分转化为可用十二烷基硫酸钠（SDS）提取的形式。SDS-聚丙烯酰胺凝胶的放射自显影片显示，三种内过氧化物可对六种疟原虫蛋白进行放射性标记。这种标记在药物的生理浓度下发生，并且不具有阶段或菌株特异性。标记的蛋白质不是考马斯亮蓝染色凝胶上最丰富的蛋白质。当用这些药物处理未感染的红细胞时，或者当用无活性类似物脱氧蒿甲醚处理感染的红细胞时，没有蛋白质被标记。因此，抗疟内过氧化物似乎与特定的疟原虫蛋白发生反应。
