Evaluation of cysteine proteases of Plasmodium vivax as antimalarial drug targets: sequence analysis and sensitivity to cysteine protease inhibitors.
Cysteine proteases perform critical roles in the life cycles of malaria parasites. In Plasmodium falciparum, treatment of cysteine protease inhibitors inhibits hemoglobin hydrolysis and blocks the parasite development in vitro and in vivo, suggesting that plasmodial cysteine proteases may be interesting targets for new chemotherapeutics. To determine whether sequence diversity may limit chemotherapy against Plasmodium vivax, we analyzed sequence variations in the genes encoding three cysteine proteases, vivapain-1, -2 and -3, in 22 wild isolates of P. vivax. The sequences were highly conserved among wild isolates. A small number of substitutions leading to amino acid changes were found, while they did not modify essential residues for the function or structure of the enzymes. The substrate specificities and sensitivities to synthetic cysteine protease inhibitors of vivapain-2 and -3 from wild isolates were also very similar. These results support the suggestion that cysteine proteases of P. vivax are promising antimalarial chemotherapeutic targets.
Na
Byoung-Kuk
BK
Department of Molecular Parasitology and Center for Molecular Medicine, Sungkyunkwan University School of Medicine and Samsung Biomedical Research Institute, Suwon 440-746, Korea.
Kim
Tong-Soo
TS
Rosenthal
Philip J
PJ
Lee
Jong-Koo
JK
Kong
Yoon
Y
D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics; D000962:Antimalarials / Q000494:pharmacology*; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D014644:Genetic Variation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D010966:Plasmodium vivax / Q000187:drug effects / Q000201:enzymology*; D015800:Protozoan Proteins / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
D000953:Antigens, Protozoan; D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D008565:Membrane Proteins; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium; D003546:Cysteine Endopeptidases