The parasite Cryptosporidium parvum is a major cause of diarrhea and malnutrition in the developing world. This disease may be prolonged and life-threatening in immune-compromised patients. Currently, no effective therapy exists for C. parvum infections. The parasite relies on inosine 5’-monophosphate dehydrogenase (IMPDH) to obtain guanine nucleotides, one of the building blocks of DNA. The parasitic enzyme (CpIMPDH) is structurally distinct from mammalian IMPDHs and is an attractive target for the development of new therapeutics.
A high-throughput screening effort identified structurally diverse, selective CpIMPDH inhibitors. Several of these compounds have been optimized to produce nanomolar inhibitors. A team of researchers, from the Center for Structural Genomics of Infectious Diseases, Brandeis University, the University of Georgia, Harvard Medical School and the University of Houston, determined the structure of CpIMPDH, in complex with its substrate, inosine 5’-monophosphate (IMP), and one optimized inhibitor, a benzoxazole-based compound Q21 (PDB id: 4IXH).
The determined structure provides a more complete understanding of IMPDH activity. For example, researchers found that the tetrameric CpIMPDH binds one molecule of inhibitor per monomer (see Figure, panel A). The inhibitor binds where two adjacent monomers meet (see Figure, panel B). This improved understanding of IMPDH activity helps researchers determine how and where inhibitor molecules bind, aiding therapeutic drug optimization.
Gorla SK, Kavitha M, Zhang M, Chin JE, Liu X, Striepen B, Makowska-Grzyska M, Kim Y, Joachimiak A, Hedstrom L, Cuny GD. Optimization of Benzoxazole-Based Inhibitors of Cryptosporidium parvum Inosine 5'-Monophosphate Dehydrogenase. J Med Chem. 2013 56(10):4028-43. PubMed PMID: 23668331
All featured structures from the NIAID Structural Genomics Centers
Last Updated July 26, 2013