期刊
ACS CHEMICAL BIOLOGY
卷 15, 期 7, 页码 1801-1807出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.0c00369
关键词
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资金
- National Institutes of Health [1R01AI144369]
- National Science Foundation Graduate Research Fellowship [174530]
- Boehringer Ingelheim Fonds PhD fellowship
- Structural Genomics Consortium
- AbbVie [1097737]
- Bayer Pharma AG [1097737]
- Boehringer Ingelheim [1097737]
- Canada Foundation for Innovation [1097737]
- Eshelman Institute for Innovation [1097737]
- Genome Canada [1097737]
- Genentech [1097737]
- Innovative Medicines Initiative (EU/EFPIA) [ULTRADD grant] [1097737, 115766]
- Janssen [1097737]
- Merck KGaA Darmstadt, Germany [1097737]
- MSD [1097737]
- Novartis Pharma AG [1097737]
- Ontario Ministry of Economic Development and Innovation [1097737]
- Pfizer [1097737]
- Sao Paulo Research Foundation-FAPESP [1097737, 2013/50724-5, 2014/5087-0, 2016/17469-0]
- Wellcome [1097737, 106169/ZZ14/Z]
- Takeda [1097737]
Apicomplexan parasites include the causative agents of malaria and toxoplasmosis. Cell-based screens in Toxoplasma previously identified a chemical modulator of calcium signaling (ENH1) that blocked parasite egress from host cells and exhibited potent antiparasitic activity. To identify the targets of ENH1, we adapted thermal proteome profiling to Toxoplasma, which revealed calcium-dependent protein kinase 1 (CDPK1) as a target. We confirmed the inhibition of CDPK1 by ENH1 in vitro and in parasites by comparing alleles sensitive or resistant to ENH1. CDPK1 inhibition explained the block in egress; however, the effects of ENH1 on calcium homeostasis and parasite viability were CDPK1-independent, implicating additional targets. Thermal proteome profiling of lysates from parasites expressing the resistant allele of CDPK1 identified additional candidates associated with the mitochondria and the parasite pellicle-compartments that potentially function in calcium release and homeostasis. Our findings illustrate the promise of thermal profiling to identify druggable targets that modulate calcium signaling in apicomplexan parasites.
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