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

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

In: Journal of Infectious Diseases, 2012, vol. 205, no. 8, p. 1278-1286

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    Titre
    • Drug Screen Targeted at Plasmodium Liver Stages Identifies a Potent Multistage Antimalarial Drug
    Auteur
    • da Cruz, Filipa P.. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal
    • Martin, Cécilie. Cenix BioScience GmbH, Dresden, Germany
    • Buchholz, Kathrin. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
    • Lafuente-Monasterio, Maria J.. Tres Cantos Medicine Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain
    • Rodrigues, Tiago. Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Switzerland
    • Sönnichsen, Birte. Cenix BioScience GmbH, Dresden, Germany
    • Moreira, Rui. iMed.UL, Faculdade de Farmácia, Universidade de Lisboa, Portugal
    • Gamo, Francisco-Javier. Tres Cantos Medicine Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain
    • Marti, Matthias. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
    • Mota, Maria M.. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal
    • Hannus, Michael. Cenix BioScience GmbH, Dresden, Germany
    • Prudêncio, Miguel. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Journal of Infectious Diseases, 2012, vol. 205, no. 8, p. 1278-1286. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:291068
    Summary
    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 bc1 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