Greenbaum, D.C. et al. A role for the protease falcipain 1 in host cell invasion by the human malaria parasite. Science 298, 2002-2006

Department of Pharmaceutical Chemistry, Veterans Affairs Medical Center, University of California, San Francisco, CA 94143, USA.
Science (Impact Factor: 33.61). 01/2003; 298(5600):2002-6. DOI: 10.1126/science.1077426
Source: PubMed


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.

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Available from: Matthew Bogyo, Sep 30, 2015
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    • "They found that in the schizont stage where the parasite invasion occurs, only one protein (Falcipain 1) showed proteolytic activity. It was later utilized in enzymatic screening of a compound library that led to the discovery of YA29-Eps, a potent blocker of the parasite invasion (Greenbaum et al. 2002). "
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    • "This compound contains an epoxide electrophilic trap that effectively inhibits cysteine proteases whose catalytic domain architecture adopts a papain-type fold, such as the cathepsins and calpain [9] [10]. Treatment of intra-erythrocytic P. falciparum parasites with E-64 results in two distinct phenotypes: a swollen food vacuole defect and an inhibition of host cell egress [11] [12]. The molecular basis of each phenotype has subsequently been determined ; the swollen food vacuole defect arises from an inability of the parasite to digest hemoglobin imported to the food vacuole from the host cell for detoxification [13]. "
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    • "During infection, the malaria parasite P. falciparum uses multiple pathways for establishment, propagation, and maintenance of the parasitaemia and chemical genetic approaches have aided in the understanding of these processes. For example, a small screen of chemical protease inhibitors targeting the Falcipain-1 protease from cell lysate was then extended in whole cell assays to identify the role of this protease in red blood cell (RBC) invasion by merozoite forms (Greenbaum et al., 2002). This provided both increased understanding of the invasion process as well as a potential new antimalarial able to prevent merozoites from entering RBCs, thereby leaving them exposed to the host immune system. "
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