title: Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins.
abstract: Residence within a customized vacuole is a highly successful strategy used by diverse intracellular microorganisms. The parasitophorous vacuole membrane (PVM) is the critical interface between Plasmodium parasites and their possibly hostile, yet ultimately sustaining, host cell environment. We show that torins, developed as ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitors, are fast-acting antiplasmodial compounds that unexpectedly target the parasite directly, blocking the dynamic trafficking of the Plasmodium proteins exported protein 1 (EXP1) and upregulated in sporozoites 4 (UIS4) to the liver stage PVM and leading to efficient parasite elimination by the hepatocyte. Torin2 has single-digit, or lower, nanomolar potency in both liver and blood stages of infection in vitro and is likewise effective against both stages in vivo, with a single oral dose sufficient to clear liver stage infection. Parasite elimination and perturbed trafficking of liver stage PVM-resident proteins are both specific aspects of torin-mediated Plasmodium liver stage inhibition, indicating that torins have a distinct mode of action compared with currently used antimalarials.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal. khanson@fm.ul.pt
authors.forename: Kirsten K
authors.initials: KK
authors.lastname: Hanson
authors.forename: Ana S
authors.initials: AS
authors.lastname: Ressurreição
authors.forename: Kathrin
authors.initials: K
authors.lastname: Buchholz
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Herman-Ornelas
authors.forename: Maria
authors.initials: M
authors.lastname: Rebelo
authors.forename: Wandy L
authors.initials: WL
authors.lastname: Beatty
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.forename: Thomas
authors.initials: T
authors.lastname: Hänscheid
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Matthias
authors.initials: M
authors.lastname: Marti
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D008099:Liver / Q000469:parasitology*; D008565:Membrane Proteins / Q000378:metabolism*; D009287:Naphthyridines / Q000494:pharmacology*; D010961:Plasmodium / Q000187:drug effects* / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism
chemical_list: C558529:9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one; D000962:Antimalarials; D008565:Membrane Proteins; D009287:Naphthyridines
keywords: P. falciparum; host-parasite interactions; malaria; protein trafficking