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Chem Biol. 2008 Jan;15(1):70-7. doi: 10.1016/j.chembiol.2007.12.010.

Targeting a prokaryotic protein in a eukaryotic pathogen: identification of lead compounds against cryptosporidiosis.

Author information

1
Department of Biochemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA.

Erratum in

  • Chem Biol. 2008 Feb;15(2):200.

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.

PMID:
18215774
PMCID:
PMC2441818
DOI:
10.1016/j.chembiol.2007.12.010
[Indexed for MEDLINE]
Free PMC Article

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