Synthesis and antiplasmodial activity of a cysteine protease-inhibiting biotinylated aziridine-2,3-dicarboxylate
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Abstract
Cysteine proteases have been implicated in a variety of processes essential for the survival and progression of the malarial parasite Plasmodium falciparum. Here, we synthesized a cysteine protease inhibitor that contains the electrophilic aziridine-2,3-dicarboxylic acid as the reactive agent and biotin as a targeting label. Diethyl ester and dibenzyl ester derivatives of the inhibitor were active against cathepsin L and the plasmodial protease falcipain 2, but only the latter displayed potent antiplasmodial activity against viable parasites. The morphological changes observed during the intraerythrocytic life stages of Plasmodium suggest that degradation of hemoglobin of the host cell is seriously affected, eventually leading to growth arrest and cell death of the parasites. After incubation of infected erythrocytes with the compound plasmodial proteins were captured, with the biotinyl group of the inhibitor serving as an affinity tag. Among these the cysteine proteases falcipain 2 and falcipain 3 were identified as potential target proteins of the compound as evidenced by tandem mass spectrometry. Apparently, the compound gets access to intracellular compartments and therein targets plasmodial cysteine proteases. Accordingly, the reagent described here appears to be a valuable template to develop cell-permeable, nonradioactive reagents that selectively target enzymes involved in pathogenicity of the parasite.
Copyright © 2004 by Walter de Gruyter GmbH & Co. KG
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Articles in the same Issue
- Publishers Note
- Role of reporter gene imaging in molecular and cellular biology
- Comprehensive search for cysteine cathepsins in the human genome
- Structure of the Q237W mutant of HhaI DNA methyltransferase: an insight into protein-protein interactions
- Identification of arginine residues important for the activity of Escherichia coli signal peptidase I
- Characterization of pancreatic ERj3p, ahomolog of yeast DnaJ-like protein Scj1p
- Carbohydrate moieties can induce mediator release: a detailed characterization of two major timothy grass pollen allergens
- The Btk inhibitor LFM-A13 is a potent inhibitor of Jak2 kinase activity
- Activation of NF-κB/Rel transcription factors in human primary peripheral blood mononuclear cells by interleukin 7
- Cystatin SA, a cysteine proteinase inhibitor, induces interferon-γ expression in CD4-positive T cells
- Inhibition of human pancreatic proteinases by human plasma α2-antiplasmin and antithrombin
- New protease inhibitors from buckwheat seeds: properties, partial amino acid sequences and possible biological role
- Synthesis and antiplasmodial activity of a cysteine protease-inhibiting biotinylated aziridine-2,3-dicarboxylate
- Cathepsins K, L, B, X and W are differentially expressed in normal and chronically inflamed gastric mucosa
