title: In Vitro Screening of the Open-Source Medicines for Malaria Venture Malaria Box Reveals Novel Compounds with Profound Activities against Theileria annulata Schizonts.
abstract: Intracellular schizonts of the apicomplexans Theileria annulata and Theileria parva immortalize bovine leukocytes and thereby cause fatal diseases. The hydroxynaphthoquinone buparvaquone is currently the only option for the treatment of theileriosis, and resistance development has been reported. It is therefore tempting to investigate the repurposing of compounds effective against related apicomplexan parasites, such as Plasmodium Here, we present the results of a screen of 400 compounds included in the open-access Medicines for Malaria Venture (MMV) malaria box on TaC12 cells, a macrophage-derived cell line immortalized by T. annulata schizonts. Using a combination of the classical alamarBlue vitality assay and a recently developed quantitative reverse transcriptase real-time PCR method based on the Theileria TaSP gene, we have identified 5 compounds, characterized their effects on the ultrastructure of TaC12 cells, and investigated whether they easily induce resistance formation. Two compounds, the quinolinols MMV666022 and MMV666054, have 50% inhibitory concentrations (IC50s) of 0.5 and 0.2 μM on TaC12 cells and 5.3 and 5.2 μM on BoMac cells, respectively. Thus, with therapeutic indexes of 11 and 18, they represent promising leads for further development of antitheilerial chemotherapeutics.
authors.affiliation: Institute for Parasitology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Hostettler
authors.affiliation: Institute for Parasitology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Joachim
authors.initials: J
authors.lastname: Müller
authors.affiliation: Institute for Parasitology, Vetsuisse Faculty, University of Bern, Bern, Switzerland andrew.hemphill@vetsuisse.unibe.ch.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hemphill
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology*; D008264:Macrophages / Q000469:parasitology; D008288:Malaria; D046529:Microscopy, Electron, Transmission; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016796:Theileria annulata / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity* / Q000648:ultrastructure
chemical_list: D000981:Antiprotozoal Agents; D006912:Hydroxyquinolines