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'-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(3) selectivity for the parasite enzyme over human IMPDH2.
authors.affiliation: Departments of Biology, Brandeis University, MS009, 415 South Street, Waltham, Massachusetts 02454, USA.
authors.forename: Iain S
authors.initials: IS
authors.lastname: Macpherson
authors.forename: Sivapriya
authors.initials: S
authors.lastname: Kirubakaran
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Gorla
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Riera
authors.forename: J Alejandro
authors.initials: JA
authors.lastname: D'Aquino
authors.forename: Minjia
authors.initials: M
authors.lastname: Zhang
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D003457:Cryptosporidiosis / Q000188:drug therapy*; D016785:Cryptosporidium parvum / Q000201:enzymology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D007168:IMP Dehydrogenase