Abstract
Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Cell Line
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Cell Proliferation / drug effects
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Coccidiostats / chemical synthesis*
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Coccidiostats / chemistry
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Coccidiostats / pharmacology
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Crystallography, X-Ray
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Drug Resistance
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Enzyme Assays
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Humans
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Models, Molecular
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Molecular Structure
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Naphthalenes / chemical synthesis
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Naphthalenes / chemistry
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Naphthalenes / pharmacology
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Piperidines / chemical synthesis
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Piperidines / chemistry
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Piperidines / pharmacology
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinases / metabolism*
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / metabolism
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Structure-Activity Relationship
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Toxoplasma / drug effects*
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Toxoplasma / enzymology
Substances
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Coccidiostats
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Naphthalenes
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Piperidines
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Protein Kinase Inhibitors
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Protozoan Proteins
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Pyrazoles
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Pyrimidines
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Protein Kinases
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calcium-dependent protein kinase