Rosenthal P J, Wollish W S, Palmer J T, Rasnick D
Department of Medicine, San Francisco General Hospital, California.
J Clin Invest. 1991 Nov;88(5):1467-72. doi: 10.1172/JCI115456.
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.
我们之前鉴定出一种恶性疟原虫滋养体半胱氨酸蛋白酶（TCP），并推测它是红细胞内疟原虫降解宿主血红蛋白所必需的。为了验证这一假设并评估TCP作为化疗靶点的可能性，我们检测了一组肽基氟甲基酮蛋白酶抑制剂的抗疟效果。对于每种抑制剂，抑制TCP活性的有效性与阻断血红蛋白降解以及杀死培养的寄生虫的有效性相关。最有效的抑制剂苄氧羰基（Z）-苯丙氨酸-精氨酸-CH2F在皮摩尔浓度下就能抑制TCP，在纳摩尔浓度下就能阻断血红蛋白降解并杀死寄生虫。微摩尔浓度的该抑制剂对培养的哺乳动物细胞无毒。这些结果支持了TCP是一种必需的血红蛋白酶这一假设，并表明它是一个有前景的化疗靶点。
