Abstract
Cysteine proteases play a crucial role in the development of the human malaria parasites Plasmodium falciparum and Plasmodium vivax. Our earlier studies demonstrated that these enzymes are equipped with specific domains for defined functions and further suggested the mechanism of activation of cysteine proteases. The activities of these proteases are regulated by a new class of endogenous inhibitors of cysteine proteases (ICPs). Structural studies of the ICPs of Trypanosoma cruzi (chagasin) and Plasmodium berghei (PbICP) indicated that three loops (termed BC, DE, and FG) are crucial for binding to target proteases. Falstatin, an ICP of P. falciparum, appears to play a crucial role in invasion of erythrocytes and hepatocytes. However, the mechanism of inhibition of cysteine proteases by falstatin has not been established. Our study suggests that falstatin is the first known ICP to function as a multimeric protein. Using site-directed mutagenesis, hemoglobin hydrolysis assays and peptide inhibition studies, we demonstrate that the BC loop, but not the DE or FG loops, inhibits cysteine proteases of P. falciparum and P. vivax via hydrogen bonds. These results suggest that the BC loop of falstatin acts as a hot-spot target for inhibiting malarial cysteine proteases. This finding suggests new strategies for the development of anti-malarial agents based on protease-inhibitor interactions.
Highlights
Plasmodium falciparum and P. vivax are the most predominant human malaria parasites worldwide
Similarity between Falstatin and Other inhibitors of cysteine proteases (ICPs) Structural studies of chagasin and PbICP led to the identification of crucial loops in the ICP family of proteins
Falstatin and its plasmodial homologues have molecular masses much higher than those of other ICPs, and so it was unclear if the structural determinants of inhibition by falstatin are similar to those of non plasmodial ICPs [11,12]
Summary
Plasmodium falciparum and P. vivax are the most predominant human malaria parasites worldwide. According to the latest WHO estimate, 219 million cases of malaria and an estimated 660,000 deaths from malaria occurred in 2010 [1]. Control measures for malaria are seriously hindered by resistance of malaria parasites to many available anti-malarial drugs [2]. Resistance against artemisinins, the most important new class of effective drugs, is emerging [3]. New anti-malarial drugs, acting against new biochemical targets, are needed. Among potential new targets for anti-malarial chemotherapy are Plasmodium proteases. Proteases are druggable targets; at present protease inhibitors are licensed and in clinical development to treat multiple diseases, including osteoporosis, diabetes, cancer, hypertension and viral infections
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