Parvanova Iana, Epiphanio Sabrina, Fauq Abdul, Golde Todd E, Prudêncio Miguel, Mota Maria M
Unidade de Malária, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
PLoS One. 2009;4(4):e5078. doi: 10.1371/journal.pone.0005078. Epub 2009 Apr 1.
The liver stage of Plasmodium's life cycle is the first, obligatory step in malaria infection. Decreasing the hepatic burden of Plasmodium infection decreases the severity of disease and constitutes a promising strategy for malaria prophylaxis. The efficacy of the gamma-secretase and signal peptide peptidase inhibitor LY411,575 in targeting Plasmodium liver stages was evaluated both in human hepatoma cell lines and in mouse primary hepatocytes. LY411,575 was found to prevent Plasmodium's normal development in the liver, with an IC(50) of approximately 80 nM, without affecting hepatocyte invasion by the parasite. In vivo results with a rodent model of malaria showed that LY411,575 decreases the parasite load in the liver and increases by 55% the resistance of mice to cerebral malaria, one of the most severe malaria-associated syndromes. Our data show that LY411,575 does not exert its effect via the Notch signaling pathway suggesting that it may interfere with Plasmodium development through an inhibition of the parasite's signal peptide peptidase. We therefore propose that selective signal peptide peptidase inhibitors could be potentially used for preventive treatment of malaria in humans.
疟原虫生命周期的肝脏阶段是疟疾感染的首个必经步骤。降低疟原虫感染的肝脏负担可减轻疾病严重程度，是一种有前景的疟疾预防策略。在人肝癌细胞系和小鼠原代肝细胞中评估了γ-分泌酶和信号肽肽酶抑制剂LY411,575靶向疟原虫肝脏阶段的功效。发现LY411,575可阻止疟原虫在肝脏中的正常发育，IC(50)约为80 nM，且不影响寄生虫对肝细胞的侵袭。疟疾啮齿动物模型的体内结果表明，LY411,575可降低肝脏中的寄生虫载量，并使小鼠对脑型疟疾（最严重的疟疾相关综合征之一）的抵抗力提高55%。我们的数据表明，LY411,575并非通过Notch信号通路发挥作用，这表明它可能通过抑制寄生虫的信号肽肽酶来干扰疟原虫的发育。因此，我们提出选择性信号肽肽酶抑制剂可能有潜力用于人类疟疾的预防性治疗。
