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Drug Screen Targeted at Plasmodium Liver Stages Identifies a Potent Multistage Antimalarial Drug

By Filipa P. da Cruz, Cécilie Martin, Maria J. Lafuente-Monasterio, Tiago Rodrigues, Birte Sönnichsen, Rui Moreira, Francisco-Javier Gamo, Michael Hannus, Miguel Prudêncio, Kathrin Buchholz, Matthias Marti and Maria Mota

Abstract

Plasmodium parasites undergo a clinically silent and obligatory developmental phase in the host’s liver cells before they are able to infect erythrocytes and cause malaria symptoms. To overcome the scarcity of compounds targeting the liver stage of malaria, we screened a library of 1037 existing drugs for their ability to inhibit Plasmodium hepatic development. Decoquinate emerged as the strongest inhibitor of Plasmodium liver stages, both in vitro and in vivo. Furthermore, decoquinate kills the parasite’s replicative blood stages and is active against developing gametocytes, the forms responsible for transmission. The drug acts by selectively and specifically inhibiting the parasite’s mitochondrial \(bc_1\) complex, with little cross-resistance with the antimalarial drug atovaquone. Oral administration of a single dose of decoquinate effectively prevents the appearance of disease, warranting its exploitation as a potent antimalarial compound

Topics: parasites
Publisher: 'Oxford University Press (OUP)'
Year: 2012
DOI identifier: 10.1093/infdis/jis184
OAI identifier: oai:dash.harvard.edu:1/8605332
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