Plasmodium falciparum signal peptide peptidase is a promising drug target against blood stage malaria.
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.
Li
Xuerong
X
Department of Pharmacology, University of Illinois College of Medicine, 909 South Wolcott Avenue, UIC Cancer Center, MC-704 Room 5100, Chicago, IL 60612, USA.
Chen
Huiqing
H
Bahamontes-Rosa
Noemi
N
Kun
Jurgen F J
JF
Traore
Boubacar
B
Crompton
Peter D
PD
Chishti
Athar H
AH
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D034741:RNA, Small Interfering / Q000235:genetics
C415363:1, 3-di-(N-carboxybenzoyl-leucyl-leucyl)amino acetone; D000962:Antimalarials; D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase