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。耐药性正在迅速使我们的抗疟疾装备过时。人类疟疾寄生虫恶性疟原虫通过在酸性食物液泡中分解宿主红细胞血红蛋白而生长。我们已经证明，天冬氨酸蛋白酶的作用通过战略性切割来解开血红蛋白分子，使其暴露于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，可杀死培养中的恶性疟原虫。这种寄生虫有四种称为血浆蛋白酶的天冬氨酸蛋白酶，它们参与食物液泡中的血红蛋白分解代谢。这些蛋白酶表现出大量的功能冗余，因此确保阻断plasmepsin的作用需要抑制所有四种蛋白酶。在不抑制宿主天冬氨酸蛋白酶的情况下靶向多种寄生虫酶是一项困难的药物设计任务。我们的策略是识别、表征并最终抑制将原质酶转化为活性形式的成熟酶。这将同时针对所有的食物液泡plasmepases，因此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希望的新药物靶点，并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.