A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase.

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dc.contributor.author Sharling, Lisa
dc.contributor.author Liu, Xiaoping
dc.contributor.author Gollapalli, Deviprasad R
dc.contributor.author Maurya, Sushil K
dc.contributor.author Hedstrom, Lizbeth
dc.contributor.author Striepen, Boris
dc.date.accessioned 2019-02-05T18:25:57Z
dc.date.available 2019-02-05T18:25:57Z
dc.date.issued 2010
dc.identifier.issn 1935-2735
dc.identifier.other PMC2919388
dc.identifier.uri https://hdl.handle.net/10192/36500
dc.description.abstract BACKGROUND: The protozoan parasite Cryptosporidium parvum is responsible for significant disease burden among children in developing countries. In addition Cryptosporidiosis can result in chronic and life-threatening enteritis in AIDS patients, and the currently available drugs lack efficacy in treating these severe conditions. The discovery and development of novel anti-cryptosporidial therapeutics has been hampered by the poor experimental tractability of this pathogen. While the genome sequencing effort has identified several intriguing new targets including a unique inosine monophosphate dehydrogenase (IMPDH), pursuing these targets and testing inhibitors has been frustratingly difficult. METHODOLOGY AND PRINCIPAL FINDINGS: Here we have developed a pipeline of tools to accelerate the in vivo screening of inhibitors of C. parvum IMPDH. We have genetically engineered the related parasite Toxoplasma gondii to serve as a model of C. parvum infection as the first screen. This assay provides crucial target validation and a large signal window that is currently not possible in assays involving C. parvum. To further develop compounds that pass this first filter, we established a fluorescence-based assay of host cell proliferation, and a C. parvum growth assay that utilizes automated high-content imaging analysis for enhanced throughput. CONCLUSIONS AND SIGNIFICANCE: We have used these assays to evaluate C. parvum IMPDH inhibitors emerging from our ongoing medicinal chemistry effort and have identified a subset of 1,2,3-triazole ethers that exhibit excellent in vivo selectivity in the T. gondii model and improved anti-cryptosporidial activity.
dc.format.extent 1 file
dc.language English
dc.language.iso eng
dc.relation.isversionof https://dx.doi.org/10.1371/journal.pntd.0000794
dc.rights Creative Commons Attribution 4.0 International License
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject Antiprotozoal Agents
dc.subject Automation
dc.subject Cryptosporidium parvum
dc.subject Drug Evaluation, Preclinical
dc.subject Enzyme Inhibitors
dc.subject High-Throughput Screening Assays
dc.subject Humans
dc.subject IMP Dehydrogenase
dc.subject Image Processing, Computer-Assisted
dc.subject Staining and Labeling
dc.subject Toxoplasma
dc.subject Triazoles
dc.title A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase.
dc.type Article
dc.contributor.department Department of Chemistry
dc.contributor.department Department of Biochemistry
dc.relation.journal PLoS Neglected Tropical Diseases
dc.identifier.pmid 20706578

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