Abstract
Cysteine proteases of Plasmodium falciparum are required for survival of the malaria parasite, yet their specific cellular functions remain unclear. We used a chemical proteomic screen with a small-molecule probe to characterize the predominant cysteine proteases throughout the parasite life cycle. Only one protease, falcipain 1, was active during the invasive merozoite stage. Falcipain 1-specific inhibitors, identified by screening of chemical libraries, blocked parasite invasion of host erythrocytes, yet had no effect on normal parasite processes such as hemoglobin degradation. These results demonstrate a specific role for falcipain 1 in host cell invasion and establish a potential new target for antimalarial therapeutics.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cysteine Endopeptidases / isolation & purification
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / chemistry
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Cysteine Proteinase Inhibitors / pharmacology
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Dose-Response Relationship, Drug
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Erythrocytes / parasitology*
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Fluorescent Antibody Technique
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Hemoglobins / metabolism
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Humans
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Leucine / analogs & derivatives*
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Leucine / pharmacology
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Life Cycle Stages
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Organelles / enzymology
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / enzymology*
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Plasmodium falciparum / growth & development
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Plasmodium falciparum / pathogenicity*
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Proteomics
Substances
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Cysteine Proteinase Inhibitors
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Hemoglobins
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Cysteine Endopeptidases
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falcipain
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falcipain 2
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falcipain 3
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Leucine
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aloxistatin