PMID- 23836641
OWN - NLM
STAT- MEDLINE
DCOM- 20131017
LR  - 20240109
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 30
DP  - 2013 Jul 23
TI  - Torins are potent antimalarials that block replenishment of Plasmodium liver 
      stage parasitophorous vacuole membrane proteins.
PG  - E2838-47
LID - 10.1073/pnas.1306097110 [doi]
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.
FAU - Hanson, Kirsten K
AU  - Hanson KK
AD  - Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 
      1649-028 Lisboa, Portugal. khanson@fm.ul.pt
FAU - Ressurreicao, Ana S
AU  - Ressurreicao AS
FAU - Buchholz, Kathrin
AU  - Buchholz K
FAU - Prudencio, Miguel
AU  - Prudencio M
FAU - Herman-Ornelas, Jonathan D
AU  - Herman-Ornelas JD
FAU - Rebelo, Maria
AU  - Rebelo M
FAU - Beatty, Wandy L
AU  - Beatty WL
FAU - Wirth, Dyann F
AU  - Wirth DF
FAU - Hanscheid, Thomas
AU  - Hanscheid T
FAU - Moreira, Rui
AU  - Moreira R
FAU - Marti, Matthias
AU  - Marti M
FAU - Mota, Maria M
AU  - Mota MM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130708
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 
      (9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one)
RN  - 0 (Antimalarials)
RN  - 0 (Membrane Proteins)
RN  - 0 (Naphthyridines)
SB  - IM
MH  - Animals
MH  - Antimalarials/*pharmacology
MH  - Liver/*parasitology
MH  - Membrane Proteins/*metabolism
MH  - Naphthyridines/*pharmacology
MH  - Plasmodium/*drug effects/metabolism
MH  - Vacuoles/metabolism
PMC - PMC3725106
OTO - NOTNLM
OT  - P. falciparum
OT  - host-parasite interactions
OT  - malaria
OT  - protein trafficking
COIS- The authors declare no conflict of interest.
EDAT- 2013/07/10 06:00
MHDA- 2013/10/18 06:00
PMCR- 2013/07/08
CRDT- 2013/07/10 06:00
PHST- 2013/07/10 06:00 [entrez]
PHST- 2013/07/10 06:00 [pubmed]
PHST- 2013/10/18 06:00 [medline]
PHST- 2013/07/08 00:00 [pmc-release]
AID - 1306097110 [pii]
AID - 201306097 [pii]
AID - 10.1073/pnas.1306097110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):E2838-47. doi: 
      10.1073/pnas.1306097110. Epub 2013 Jul 8.