BACKGROUND The malaria parasite Plasmodium falciparum expresses four related papain-family cysteine proteases known as falcipains. These proteases play critical roles in the parasite life cycle, and as such are potential targets for new modes of antimalarial chemotherapy, as discussed in this review. SCOPE OF REVIEW This review summarizes available knowledge describing falcipain cysteine proteases of malaria parasites. MAJOR CONCLUSIONS Based on available data the falcipains can be broken into two sub-families, the falcipain-1 and the falcipain-2/3 sub-families. Falcipain-1 has been difficult to study; it appears to play its most important roles in nonerythrocytic parasites, but not the erythrocytic stage responsible for human disease. Falcipain-2 and falcipain-3 have similar biochemical features, and are expressed sequentially during the erythrocytic cycle. Inhibition of either of these enzymes blocks hemoglobin hydrolysis and completion of the parasite developmental cycle. Knockout of falcipain-2 blocks hemoglobin hydrolysis, but parasites recover, presumably due to subsequent expression of falcipain-3. Knockout of falcipain-3 has not been possible, suggesting that the protease is essential for erythrocytic parasites. Determination of structures of falcipains and extensive chemistry efforts have facilitated identification of numerous small molecule falcipain inhibitors as potential new antimalarial agents. Other malaria parasites express close homologs of falcipain-1 and falcipain-2/3 proteases, suggesting that agents that target the falcipains will also be active against other human malaria parasites. GENERAL SIGNIFICANCE Falcipain-2 and falcipain-3 play vital roles during the erythrocytic stage of infection with P. falciparum and thus are promising targets for new agents to treat malaria.

中文翻译：

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疟原虫的Falcipain半胱氨酸蛋白酶：更新。

背景技术疟原虫恶性疟原虫表达四种相关的木瓜蛋白酶家族半胱氨酸蛋白酶，被称为恶性肽。这些蛋白酶在寄生虫的生命周期中起着至关重要的作用，因此是抗疟疾化学疗法新模式的潜在靶点，如本综述所述。综述的范围这篇综述总结了描述疟原虫的恶性福西汀半胱氨酸蛋白酶的可用知识。主要结论根据现有数据，falcipains可分为两个亚家族：falcipain-1和falcipain-2 / 3亚家族。Falcipain-1很难研究。它似乎在非红细胞寄生虫中发挥着最重要的作用，但不是导致人类疾病的红细胞阶段。Falcipain-2和falcipain-3具有相似的生化特征，并且在红细胞周期中顺序表达。这些酶中任一种的抑制作用均会阻止血红蛋白水解并完成寄生虫发育周期。敲除falcipain-2可阻止血红蛋白水解，但寄生虫得以恢复，大概是由于falcipain-3的后续表达所致。尚不可能敲除falcipain-3，这表明该蛋白酶对于红细胞寄生虫至关重要。法利沙星的结构测定和广泛的化学努力促进了许多小分子法利沙星抑制剂作为潜在的新型抗疟药的鉴定。其他疟疾寄生虫表达falcipain-1和falcipain-2 / 3蛋白酶的紧密同源物，这表明靶向falcipains的药物也具有对抗其他人类疟疾寄生虫的活性。