Characterization of Proplasmepsin Maturase

描述（由申请人提供）：疟疾是世界上最具破坏性的疾病之一。抗药性正在迅速使我们的抗疟武器过时。人类疟原虫恶性疟原虫通过分解代谢宿主红细胞血红蛋白在其酸性食物泡中生长。我们已经表明，天冬氨酸蛋白酶的行动解开血红蛋白分子的战略切割，使其进一步，有效的蛋白水解。阻断血红蛋白降解的天冬氨酸蛋白酶抑制剂，杀死培养物中的恶性疟原虫。该寄生虫有四种天冬氨酸蛋白酶，称为plasmepsin，参与食物泡中的血红蛋白催化。这些蛋白酶表现出大量的功能冗余，因此确保阻断纤溶酶作用需要抑制所有四种。这是一项困难的药物设计任务，靶向多种寄生虫酶而不抑制宿主天冬氨酸蛋白酶。我们的策略是识别、表征并最终抑制将pro-plasmepsin转化为其活性形式的成熟酶。这将同时靶向所有的食物空泡胞浆蛋白酶，因此也是血红蛋白降解的关键过程。从我们的研究中获得的结果应该定义一个有前途的新药靶点，着眼于未来的药物开发。

DESCRIPTION (provided by the applicant): Malaria is one of the world's most devastating diseases. Drug resistance is rapidly rendering our antimalarial armamentarium obsolete. The human malaria parasite Plasmodium falciparum grows by catabolizing host erythrocyte hemoglobin in its acidic food vacuole. We have shown that aspartic protease action unravels the hemoglobin molecule by strategic cleavage, exposing it for further, efficient proteolysis. Aspartic protease inhibitors that block hemoglobin degradation, kill P.falciparum parasites in culture. The parasite has four aspartic proteases called plasmepsins that participate in hemoglobin catabolism in the food vacuole. These proteases exhibit substantial functional redundancy, so ensuring blockade of plasmepsin action requires inhibition of all four. This is a difficult drug design task, to target the multiple parasite enzymes without inhibiting host aspartic proteases. Our strategy is to identify, characterize and ultimately inhibit the maturase that converts pro-plasmepsins to their active form. This will simultaneously target all the food vacuole plasmepsins and therefore the crucial process of hemoglobin degradation. The results obtained from our study should define a promising new drug target, with an eye towards future drug development.