Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antimalarial endoperoxides, N-89 and N-251.
The endoperoxide artemisinin is a current first-line antimalarial and a critical component of the artemisinin-based combination therapies (ACT) recommended by WHO for treatment of Plasmodium falciparum, the deadliest of malaria parasites. However, recent emergence of the artemisinin-resistant P. falciparum urged us to develop new antimalarial drugs. We have shown that synthetic endoperoxides N-89 and its hydroxyl derivative N-251 had high antimalarial activities both in vivo and in vitro. However, the mechanisms including the cellular targets of the endoperoxide antimalarials are not well understood. Thus, in this study, we employed chemical proteomics to survey potential molecular targets of endoperoxides by evaluating P. falciparum proteins capable to associate with endoperoxide structure (N-346, a carboxyamino derivative of N-89). We also analyzed the protein expression profiles of malaria parasites treated with N-89 or N-251 to explore possible changes associated with the drug action. From these experiments, we found that P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC) had high affinity to the endoperoxide structure (N-346) and was decreased by treatment with N-89 or N-251. PfERC is a member of CREC protein family, a potential disease marker and also a potential target for therapeutic intervention. We propose that the PfERC is a strong candidate of the endoperoxide antimalarial's target.
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700-8530, Japan.
Masayuki
M
Morita
Hitomi
H
Sanai
Akiko
A
Hiramoto
Akira
A
Sato
Osamu
O
Hiraoka
Takaya
T
Sakura
Osamu
O
Kaneko
Araki
A
Masuyama
Masatomo
M
Nojima
Yusuke
Y
Wataya
Hye-Sook
HS
Kim
D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000737:chemistry*; D002846:Chromatography, Affinity; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000737:chemistry*; D004912:Erythrocytes / Q000469:parasitology; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D006801:Humans; D010545:Peroxides / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000737:chemistry* / Q000187:drug effects / Q000472:pathogenicity; D040901:Proteomics / Q000379:methods; D015800:Protozoan Proteins / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013141:Spiro Compounds / Q000494:pharmacology; D045568:Tetraoxanes / Q000494:pharmacology; D053058:Trophozoites / Q000737:chemistry / Q000187:drug effects
C430901:1,2,6,7-tetraoxaspiro(7.11)nonadecane; C571809:6-(1,2,6,7-tetraoxaspiro(7.11)nonadec-4-yl)hexan-1-ol; D000962:Antimalarials; D002135:Calcium-Binding Proteins; D006574:Heterocyclic Compounds, 2-Ring; D010545:Peroxides; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D013141:Spiro Compounds; D045568:Tetraoxanes