ArticlePLoS pathogens2014
Forward genetic screening identifies a small molecule that blocks Toxoplasma gondii growth by inhibiting both host- and parasite-encoded kinases.
Article in PLoS pathogens, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 45 citations in OpenAlex.
- Kinase inhibitors in organoid media influenceMicrobiology spectrum · 2026Article
- The cell cycle-regulated cytoplasmic kinase, TgCRCK1, is required for efficient propagation of human protozoan pathogen,Microbiology spectrum · 2026Article
- Deciphering cell cycle organization ofmBio · 2025Article
- Versatile Imidazole Scaffold with Potent Activity against Multiple Apicomplexan Parasites.ACS infectious diseases · 2025Article
- Bumped Kinase Inhibitors Inhibit bothACS infectious diseases · 2025Article
- The Toxoplasma oxygen-sensing protein, TgPhyA, is required for resistance to interferon gamma-mediated nutritional immunity in mice.PLoS biology · 2024Article
- The Crk4-Cyc4 complex regulates GThe EMBO journal · 2024Article
- Regulatory Functions of Hypoxia in Host-Parasite Interactions: A Focus on Enteric, Tissue, and Blood Protozoa.Microorganisms · 2023Review
- Not your Mother's MAPKs: Apicomplexan MAPK function in daughter cell budding.PLoS pathogens · 2022Review
- Protein kinases in Toxoplasma gondii.International journal for parasitology · 2021Review
- Dual-Stage Picolinic Acid-Derived Inhibitors ofACS medicinal chemistry letters · 2020Article
- Fussing About Fission: Defining Variety Among Mainstream and Exotic Apicomplexan Cell Division Modes.Frontiers in cellular and infection microbiology · 2020Article
- Toxoplasma F-box protein 1 is required for daughter cell scaffold function during parasite replication.PLoS pathogens · 2019Article
- Who Needs a Contractile Actomyosin Ring? The Plethora of Alternative Ways to Divide a Protozoan Parasite.Frontiers in cellular and infection microbiology · 2019Review
- The Activin Receptor, Activin-Like Kinase 4, MediatesFrontiers in cellular and infection microbiology · 2019Article
- TgTKL1 Is a Unique Plant-Like Nuclear Kinase That Plays an Essential Role in Acute Toxoplasmosis.mBio · 2018Article
- HIF-1α is a key regulator in potentiating suppressor activity and limiting the microbicidal capacity of MDSC-like cells during visceral leishmaniasis.PLoS pathogens · 2017Article
- The coccidian parasitesThe Journal of biological chemistry · 2017Article
- The p38 MAPK inhibitor, SB203580, inhibits cell invasion by Neospora caninum.Parasitology research · 2017Article
- Activation of aFrontiers in microbiology · 2017Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 1 country.
Funding
Abstract
The simultaneous targeting of host and pathogen processes represents an untapped approach for the treatment of intracellular infections. Hypoxia-inducible factor-1 (HIF-1) is a host cell transcription factor that is activated by and required for the growth of the intracellular protozoan parasite Toxoplasma gondii at physiological oxygen levels. Parasite activation of HIF-1 is blocked by inhibiting the family of closely related Activin-Like Kinase (ALK) host cell receptors ALK4, ALK5, and ALK7, which was determined in part by use of an ALK4,5,7 inhibitor named SB505124. Besides inhibiting HIF-1 activation, SB505124 also potently blocks parasite replication under normoxic conditions. To determine whether SB505124 inhibition of parasite growth was exclusively due to inhibition of ALK4,5,7 or because the drug inhibited a second kinase, SB505124-resistant parasites were isolated by chemical mutagenesis. Whole-genome sequencing of these mutants revealed mutations in the Toxoplasma MAP kinase, TgMAPK1. Allelic replacement of mutant TgMAPK1 alleles into wild-type parasites was sufficient to confer SB505124 resistance. SB505124 independently impacts TgMAPK1 and ALK4,5,7 signaling since drug resistant parasites could not activate HIF-1 in the presence of SB505124 or grow in HIF-1 deficient cells. In addition, TgMAPK1 kinase activity is inhibited by SB505124. Finally, mice treated with SB505124 had significantly lower tissue burdens following Toxoplasma infection. These data therefore identify SB505124 as a novel small molecule inhibitor that acts by inhibiting two distinct targets, host HIF-1 and TgMAPK1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.