Abstract
Cryptosporidium parvum is an important human pathogen and potential bioterrorism agent. No vaccines exist against C. parvum, the drugs currently approved to treat cryptosporidiosis are ineffective, and drug discovery is challenging because the parasite cannot be maintained continuously in cell culture. Mining the sequence of the C. parvum genome has revealed that the only route to guanine nucleotides is via inosine-5'-monophosphate dehydrogenase (IMPDH). Moreover, phylogenetic analysis suggests that the IMPDH gene was obtained from bacteria by lateral gene transfer. Here we exploit the unexpected evolutionary divergence of parasite and host enzymes by designing a high-throughput screen to target the most diverged portion of the IMPDH active site. We have identified four parasite-selective IMPDH inhibitors that display antiparasitic activity with greater potency than paromomycin, the current gold standard for anticryptosporidial activity.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antiparasitic Agents / chemistry
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Antiparasitic Agents / pharmacology
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Antiparasitic Agents / therapeutic use*
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Binding Sites
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Cryptosporidiosis / drug therapy*
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Cryptosporidiosis / enzymology
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Cryptosporidium parvum / drug effects*
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Cryptosporidium parvum / enzymology
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Cryptosporidium parvum / pathogenicity
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Eukaryotic Cells / enzymology*
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Guanine Nucleotide Dissociation Inhibitors / chemistry
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Guanine Nucleotide Dissociation Inhibitors / pharmacology
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Guanine Nucleotide Dissociation Inhibitors / therapeutic use
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Guanine Nucleotides / metabolism
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Humans
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IMP Dehydrogenase / antagonists & inhibitors*
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IMP Dehydrogenase / chemistry
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IMP Dehydrogenase / metabolism
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Kinetics
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Paromomycin / chemistry
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Paromomycin / pharmacology
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Paromomycin / therapeutic use
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Prokaryotic Cells / enzymology*
Substances
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Antiparasitic Agents
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Guanine Nucleotide Dissociation Inhibitors
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Guanine Nucleotides
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Paromomycin
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IMP Dehydrogenase