title: The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei.
abstract: The protozoan parasite Trypanosoma brucei causes human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills different T. brucei spp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca(2+), and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significant in vitro activity against T. brucei.
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, PTS Granada, Granada, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Carvalho
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, PTS Granada, Granada, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Martínez-García
authors.affiliation: Fundación Medina, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, PTS Granada, Granada, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Pérez-Victoria
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, PTS Granada, Granada, Spain.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Manzano
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, PTS Granada, Granada, Spain josepv@ipb.csic.es gamarro@ipb.csic.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, PTS Granada, Granada, Spain josepv@ipb.csic.es gamarro@ipb.csic.es.
authors.forename: José M
authors.initials: JM
authors.lastname: Pérez-Victoria
mesh_terms: D000284:Administration, Oral; D000634:Aminoquinolines / Q000378:metabolism / Q000494:pharmacology*; D000962:Antimalarials / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; C055852:tafenoquine