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

• Published in: The Journal of infectious diseases Vol. 205; no. 8; pp. 1278 - 1286
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.04.2012
• Subjects: Animals; Antimalarials; Antimalarials - pharmacology; Atovaquone - pharmacology; Biological and medical sciences; Blood; Cell Line, Tumor; Cell lines; Cytochromes; Decoquinate - pharmacology; Drug Evaluation, Preclinical - methods; Fundamental and applied biological sciences. Psychology; Hepatocytes - parasitology; Humans; Infections; Infectious diseases; Inhibitory concentration 50; Liver; Major and Brief Reports; Malaria; Malaria - drug therapy; Malaria - parasitology; Medical sciences; Microbiology; Mitochondria - drug effects; Mitochondria - metabolism; Models, Molecular; Molecular Structure; Parasites; Plasmodium - drug effects; Preclinical drug evaluation; Protein Conformation; Infection; Protozoa; Plasmodium; Apicomplexa; Digestive system; Liver; Identification
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jis184

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.