Semenov A, Olson J E, Rosenthal P J
Department of Medicine, San Francisco General Hospital and University of California, San Francisco, California, USA.
Antimicrob Agents Chemother. 1998 Sep;42(9):2254-8. doi: 10.1128/AAC.42.9.2254.
It has been proposed that the Plasmodium falciparum cysteine protease falcipain and aspartic proteases plasmepsin I and plasmepsin II act cooperatively to hydrolyze hemoglobin as a source of amino acids for erythrocytic parasites. Inhibitors of each of these proteases have potent antimalarial effects. We have now evaluated the antimalarial effects of combinations of cysteine and aspartic protease inhibitors. When incubated with cultured P. falciparum parasites, cysteine and aspartic protease inhibitors exhibited synergistic effects in blocking parasite metabolism and development. The inhibitors also demonstrated apparent synergistic inhibition of plasmodial hemoglobin degradation both in culture and in a murine malaria model. When evaluated for the treatment of murine malaria, a combination of cysteine and aspartic protease inhibitors was much more effective than higher concentrations of either compound used alone. These results support a model whereby plasmodial cysteine and aspartic proteases participate in the degradation of hemoglobin, and they suggest that combination antimalarial therapy with inhibitors of the two classes of proteases is worthy of further study.
有人提出，恶性疟原虫半胱氨酸蛋白酶疟原虫蛋白酶和天冬氨酸蛋白酶疟原虫胃蛋白酶I和疟原虫胃蛋白酶II协同作用，水解血红蛋白，为红细胞内寄生虫提供氨基酸来源。这些蛋白酶的每种抑制剂都有强大的抗疟作用。我们现在评估了半胱氨酸和天冬氨酸蛋白酶抑制剂组合的抗疟效果。当与培养的恶性疟原虫寄生虫一起孵育时，半胱氨酸和天冬氨酸蛋白酶抑制剂在阻断寄生虫代谢和发育方面表现出协同作用。这些抑制剂在培养物和小鼠疟疾模型中也表现出对疟原虫血红蛋白降解的明显协同抑制作用。当评估对小鼠疟疾的治疗效果时，半胱氨酸和天冬氨酸蛋白酶抑制剂的组合比单独使用较高浓度的任何一种化合物都有效得多。这些结果支持了一种模型，即疟原虫半胱氨酸和天冬氨酸蛋白酶参与血红蛋白的降解，并且它们表明用这两类蛋白酶的抑制剂进行联合抗疟治疗值得进一步研究。
