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Title: The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity

Cryptosporidium parvum is a potential biowarfare agent, an important AIDS pathogen, and a major cause of diarrhea and malnutrition. No vaccines or effective drug treatment exist to combat Cryptosporidium infection. This parasite relies on inosine 5{prime}-monophosphate dehydrogenase (IMPDH) to obtain guanine nucleotides, and inhibition of this enzyme blocks parasite proliferation. Here, we report the first crystal structures of CpIMPDH. These structures reveal the structural basis of inhibitor selectivity and suggest a strategy for further optimization. Using this information, we have synthesized low-nanomolar inhibitors that display 10{sup 3} selectivity for the parasite enzyme over human IMPDH2.
Authors:
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  1. (BWH)
  2. (
Publication Date:
OSTI Identifier:
1002265
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Am. Chem. Soc.; Journal Volume: 132; Journal Issue: (4) ; 02, 2010
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; CRYSTAL STRUCTURE; DIARRHEA; ENZYMES; GUANINE; INOSINE; NUCLEOTIDES; NUTRITIONAL DEFICIENCY; OPTIMIZATION; OXIDOREDUCTASES; PARASITES; PROLIFERATION; VACCINES