skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

Abstract

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:
; ; ; ; ; ; ;  [1];  [2]
  1. (BWH)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002265
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Am. Chem. Soc.; Journal Volume: 132; Journal Issue: (4) ; 02, 2010
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

Citation Formats

MacPherson, Iain S., Kirubakaran, Sivapriya, Gorla, Suresh Kumar, Riera, Thomas V., D’Aquino, J. Alejandro, Zhang, Minjia, Cuny, Gregory D., Hedstrom, Lizbeth, and Brandeis). The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity. United States: N. p., 2010. Web. doi:10.1021/ja909947a.
MacPherson, Iain S., Kirubakaran, Sivapriya, Gorla, Suresh Kumar, Riera, Thomas V., D’Aquino, J. Alejandro, Zhang, Minjia, Cuny, Gregory D., Hedstrom, Lizbeth, & Brandeis). The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity. United States. doi:10.1021/ja909947a.
MacPherson, Iain S., Kirubakaran, Sivapriya, Gorla, Suresh Kumar, Riera, Thomas V., D’Aquino, J. Alejandro, Zhang, Minjia, Cuny, Gregory D., Hedstrom, Lizbeth, and Brandeis). 2010. "The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity". United States. doi:10.1021/ja909947a.
@article{osti_1002265,
title = {The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity},
author = {MacPherson, Iain S. and Kirubakaran, Sivapriya and Gorla, Suresh Kumar and Riera, Thomas V. and D’Aquino, J. Alejandro and Zhang, Minjia and Cuny, Gregory D. and Hedstrom, Lizbeth and Brandeis)},
abstractNote = {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.},
doi = {10.1021/ja909947a},
journal = {J. Am. Chem. Soc.},
number = (4) ; 02, 2010,
volume = 132,
place = {United States},
year = 2010,
month = 3
}