Pandey Kailash C
Host-Parasite Interaction Biology Group, National Institute of Malaria Research, Indian Council of Medical Research, Sector-8, Dwarka, New Delhi, 110077 India.
J Parasit Dis. 2011 Oct;35(2):94-103. doi: 10.1007/s12639-011-0084-x. Epub 2011 Dec 3.
There is an urgent need for new drugs against malaria, which takes millions of lives annually. Cysteine proteases are potential new drug targets, especially when current drugs are showing resistance. Falcipains and vivapains are well characterized cysteine proteases of P. falciparum and P. vivax, respectively. Studies with cysteine protease inhibitors and manipulating cysteine proteases specific genes have suggested their roles in hemoglobin hydrolysis. In P. falciparum, falcipain-2 and falcipain-3 are major hemoglobinases that hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. It is confirmed that disruption of the falcipain-2 gene led to a transient block in hemoglobin hydrolysis, and disruption of falcipain-3 gene was not possible, suggesting that protease is essential for erythrocytic parasites. On the other hand, vivapain-2, vivapain-3 and vivapain-4 are important cysteine proteases of P. vivax, which shared a number of features with falcipain-2 and falcipain-3. A recent study indicates that vivapains and aspartic protease of P. vivax works collaboratively to enhance the parasites' ability to hydrolyze host erythrocyte hemoglobin. Studies also indicate that falcipains and vivapains also hydrolyse the erythrocyte cytoskeleton proteins and involved in rupture of red blood cell. Structural and biochemical analysis of falcipains and vivapains showed that they have unique domains for specific functions. Overall, the complexes of cysteine proteases with small and macromolecular inhibitors provide structural insight to facilitate the drug design. Therefore, giving due importance to the cysteine proteases, this review will briefly focus the recent advancement in the field of cysteine proteases of human malaria parasites.
每年有数百万人死于疟疾，因此迫切需要研发新型抗疟药物。半胱氨酸蛋白酶是潜在的新药靶点，尤其是在当前药物已出现耐药性的情况下。恶性疟原虫的法氏蛋白酶和间日疟原虫的间日蛋白酶分别是已得到充分研究的半胱氨酸蛋白酶。使用半胱氨酸蛋白酶抑制剂以及对特定半胱氨酸蛋白酶基因进行操作的研究表明，它们在血红蛋白水解过程中发挥作用。在恶性疟原虫中，法氏蛋白酶-2和法氏蛋白酶-3是主要的血红蛋白酶，可在寄生虫的食物泡中水解宿主红细胞血红蛋白。已证实，法氏蛋白酶-2基因的破坏会导致血红蛋白水解过程出现短暂阻断，而法氏蛋白酶-3基因无法被破坏，这表明该蛋白酶对于红细胞内的寄生虫至关重要。另一方面，间日蛋白酶-2、间日蛋白酶-3和间日蛋白酶-4是间日疟原虫重要的半胱氨酸蛋白酶，它们与法氏蛋白酶-2和法氏蛋白酶-3具有许多共同特征。最近的一项研究表明，间日疟原虫的间日蛋白酶和天冬氨酸蛋白酶协同作用，可增强寄生虫水解宿主红细胞血红蛋白的能力。研究还表明，法氏蛋白酶和间日蛋白酶也可水解红细胞细胞骨架蛋白，并参与红细胞破裂过程。对法氏蛋白酶和间日蛋白酶的结构和生化分析表明，它们具有执行特定功能的独特结构域。总体而言，半胱氨酸蛋白酶与小分子和大分子抑制剂的复合物为药物设计提供了结构方面的见解。因此，鉴于半胱氨酸蛋白酶的重要性，本综述将简要聚焦人类疟原虫半胱氨酸蛋白酶领域的最新进展。
