Inhibition of Plasmodium falciparum cysteine proteases by the sugarcane cystatin CaneCPI-4 |
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Authors: | Pollyana M.S. Melo Sarah El Chamy Maluf Mauro F. Azevedo Thaysa Paschoalin Alexandre Budu Piero Bagnaresi Flávio Henrique-Silva Andrea Soares-Costa Marcos L. Gazarini Adriana K. Carmona |
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Affiliation: | 1. Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, Brazil;2. Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil;3. Departamento de Biociências, Universidade Federal de São Paulo, Santos, Brazil |
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Abstract: | Malaria is a disease caused by Plasmodium parasites that affects hundreds of millions of people. Plasmodium proteases are involved in invasion, erythrocyte egress and degradation of host proteins. Falcipains are well-studied cysteine peptidases located in P. falciparum food vacuoles that participate in hemoglobin degradation. Cystatins are natural cysteine protease inhibitors that are implicated in a wide range of regulatory processes. Here, we report that a cystatin from sugarcane, CaneCPI-4, is selectively internalized into P. falciparum infected erythrocytes and is not processed by the parasite proteolytic machinery. Furthermore, we demonstrated the inhibition of P. falciparum cysteine proteases by CaneCPI-4, suggesting that it can exert inhibitory functions inside the parasites. The inhibition of the proteolytic activity of parasite cells is specific to this cystatin, as the addition of an anti-CaneCPI-4 antibody completely abolished the inhibition. We extended the studies to recombinant falcipain-2 and falcipain-3 and demonstrated that CaneCPI-4 strongly inhibits these enzymes, with IC50 values of 12 nM and 42 nM, respectively. We also demonstrated that CaneCPI-4 decreased the hemozoin formation in the parasites, affecting the parasitemia. Taken together, this study identified a natural molecule as a potential antimalarial that specifically targets falcipains and also contributes to a better understanding of macromolecule acquisition by Plasmodium falciparum infected RBCs. |
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Keywords: | Cysteine protease Falcipain Canecystatin Inhibition |
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