title: Drug screen targeted at Plasmodium liver stages identifies a potent multistage antimalarial drug.
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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal.
authors.forename: Filipa P
authors.initials: FP
authors.lastname: da Cruz
authors.forename: Cécilie
authors.initials: C
authors.lastname: Martin
authors.forename: Kathrin
authors.initials: K
authors.lastname: Buchholz
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Lafuente-Monasterio
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.forename: Birte
authors.initials: B
authors.lastname: Sönnichsen
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gamo
authors.forename: Matthias
authors.initials: M
authors.lastname: Marti
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.forename: Michael
authors.initials: M
authors.lastname: Hannus
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone / Q000494:pharmacology; D045744:Cell Line, Tumor; D003667:Decoquinate / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D022781:Hepatocytes / Q000469:parasitology*; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010961:Plasmodium / Q000187:drug effects*; D011487:Protein Conformation
chemical_list: D000962:Antimalarials; D003667:Decoquinate; D053626:Atovaquone