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Science 6 December 2002:
Vol. 298. no. 5600, pp. 2002 - 2006
DOI: 10.1126/science.1077426
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Reports

A Role for the Protease Falcipain 1 in Host Cell Invasion by the Human Malaria Parasite

Doron C. Greenbaum,1* Amos Baruch,2 Munira Grainger,4 Zbynek Bozdech,2 Katlin F. Medzihradszky,1 Juan Engel,3 Joseph DeRisi,2 Anthony A. Holder,4 Matthew Bogyo2*

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.

1 Department of Pharmaceutical Chemistry,
2 Department of Biochemistry and Biophysics,
3 Department of Pathology, Veterans Affairs Medical Center, University of California, San Francisco, CA 94143, USA.
4 Division of Parasitology, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
*   To whom correspondence should be addressed at M. Bogyo, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94043, USA. E-mail: dgreenb{at}itsa.ucsf.edu (D.C.G.) and mbogyo{at}biochem.ucsf.edu (M.B.)

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