Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins

Kirsten K. Hanson, Ana S. Ressurreicao, Kathrin Buchholz, Miguel Prudencio, Jonathan D. Herman-Ornelas, Maria Rebelo, Wandy L. Beatty, Dyann F. Wirth, Thomas Hanscheid, Rui Moreira, Matthias Marti, Maria M. Mota

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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.

Original languageEnglish
Pages (from-to)E2838-E2847
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number30
DOIs
StatePublished - Jul 23 2013

Keywords

  • Host-parasite interactions
  • Malaria
  • P. falciparum
  • Protein trafficking

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