TY - JOUR
T1 - Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins
AU - Hanson, Kirsten K.
AU - Ressurreicao, Ana S.
AU - Buchholz, Kathrin
AU - Prudencio, Miguel
AU - Herman-Ornelas, Jonathan D.
AU - Rebelo, Maria
AU - Beatty, Wandy L.
AU - Wirth, Dyann F.
AU - Hanscheid, Thomas
AU - Moreira, Rui
AU - Marti, Matthias
AU - Mota, Maria M.
PY - 2013/7/23
Y1 - 2013/7/23
N2 - 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.
AB - 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.
KW - Host-parasite interactions
KW - Malaria
KW - P. falciparum
KW - Protein trafficking
UR - http://www.scopus.com/inward/record.url?scp=84880650998&partnerID=8YFLogxK
U2 - 10.1073/pnas.1306097110
DO - 10.1073/pnas.1306097110
M3 - Article
C2 - 23836641
AN - SCOPUS:84880650998
VL - 110
SP - E2838-E2847
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 30
ER -