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Targeting a prokaryotic protein in a eukaryotic pathogen: identification of lead
compounds against Cryptosporidiosis
Nwakaso N. Umejiego, Deviprasad Gollapalli, Lisa Sharling, Anna Volftsun, Jennifer Lu, Nicole
N. Benjamin, Adam H. Stroupe, Thomas V. Riera, Boris Striepen and Lizbeth Hedstrom
Chem Biol. 2008 Jan;15(1):70-7.
Cryptosporidium parvum is a major cause of
the "vicious cycle of diarrhea and
malnutrition" in the developing world. In the
developed world, this eukaryotic parasite is
an important AIDS pathogen and potential
bio-terrorism 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, 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.
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Voice of America interview:
Science Daily article
Cryptosporidium blog:
Faculty of 1000: