Li Xuerong, Chen Huiqing, Bahamontes-Rosa Noemi, Kun Jurgen F J, Traore Boubacar, Crompton Peter D, Chishti Athar H
Department of Pharmacology, University of Illinois College of Medicine, 909 South Wolcott Avenue, UIC Cancer Center, MC-704 Room 5100, Chicago, IL 60612, USA.
Biochem Biophys Res Commun. 2009 Mar 13;380(3):454-9. doi: 10.1016/j.bbrc.2009.01.083. Epub 2009 Jan 25.
The resistance of malaria parasites to current anti-malarial drugs is an issue of major concern globally. Recently we identified a Plasmodium falciparum cell membrane aspartyl protease, which binds to erythrocyte band 3, and is involved in merozoite invasion. Here we report the complete primary structure of P. falciparum signal peptide peptidase (PfSPP), and demonstrate that it is essential for parasite invasion and growth in human erythrocytes. Gene silencing suggests that PfSPP may be essential for parasite survival in human erythrocytes. Remarkably, mammalian signal peptide peptidase inhibitors (Z-LL)(2)-ketone and L-685,458 effectively inhibited malaria parasite invasion as well as growth in human erythrocytes. In contrast, DAPT, an inhibitor of a related gamma-secretase/presenilin-1, was ineffective. Thus, SPP inhibitors specific for PfSPP may function as potent anti-malarial drugs against the blood stage malaria.
疟原虫对现有抗疟药物的耐药性是全球主要关注的问题。最近我们鉴定出一种恶性疟原虫细胞膜天冬氨酰蛋白酶，它与红细胞带3结合，并参与裂殖子入侵。在此我们报道恶性疟原虫信号肽肽酶（PfSPP）的完整一级结构，并证明它对于疟原虫在人红细胞中的入侵和生长至关重要。基因沉默表明PfSPP可能对疟原虫在人红细胞中的存活至关重要。值得注意的是，哺乳动物信号肽肽酶抑制剂（Z-LL）(2)-酮和L-685,458有效抑制疟原虫入侵以及在人红细胞中的生长。相比之下，相关γ-分泌酶/早老素-1的抑制剂DAPT则无效。因此，对PfSPP具有特异性的SPP抑制剂可能作为针对血液期疟疾的有效抗疟药物发挥作用。
