ArticleProceedings of the National Academy of Sciences of the United States of America2013
Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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50 citing papers in PubMed, 84 citations in OpenAlex.
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- A Pyridyl-Furan Series Developed from the Open Global Health Library Block Red Blood Cell Invasion and Protein Trafficking inACS infectious diseases · 2023Article
- Human Polo-like Kinase Inhibitors as Antiplasmodials.ACS infectious diseases · 2023Article
- Autophagy in protists and their hosts: When, how and why?Autophagy reports · 2023Article
- Capsaicin decreases fecundity in the Asian malaria vector Anopheles stephensi by inhibiting the target of rapamycin signaling pathway.Parasites & vectors · 2022Article
- The Medicines for Malaria Venture Malaria Box contains inhibitors of protein secretion in Plasmodium falciparum blood stage parasites.Traffic (Copenhagen, Denmark) · 2022Article
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- Maria M. Mota: BringingFrontiers in cellular and infection microbiology · 2022Article
- Rapamycin inhibits pathogen transmission in mosquitoes by promoting immune activation.PLoS pathogens · 2021Article
- Plasmodium berghei sporozoites in nonreplicative vacuole are eliminated by a PI3P-mediated autophagy-independent pathway.Cellular microbiology · 2021Article
- Repurposing bioenergetic modulators against protozoan parasites responsible for tropical diseases.International journal for parasitology. Drugs and drug resistance · 2020Article
- Disrupting Plasmodium UIS3-host LC3 interaction with a small molecule causes parasite elimination from host cells.Communications biology · 2020Article
- Plasmodium translocon component EXP2 facilitates hepatocyte invasion.Nature communications · 2020Article
- Torin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition ofACS pharmacology & translational science · 2020Article
- Plasmodium vivax liver stage assay platforms using Indian clinical isolates.Malaria journal · 2020Article
- A crucial role for the C-terminal domain of exported protein 1 during the mosquito and hepatic stages of the Plasmodium berghei life cycle.Cellular microbiology · 2019Article
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Authors and funding
12 authors at 3 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
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.
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