A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase.
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 s...
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ftdoajarticles:oai:doaj.org/article:c82cebf4ac364fa59487e8aa18574021 2023-05-15T15:09:53+02:00 A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase. Lisa Sharling Xiaoping Liu Deviprasad R Gollapalli Sushil K Maurya Lizbeth Hedstrom Boris Striepen 2010-08-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0000794 https://doaj.org/article/c82cebf4ac364fa59487e8aa18574021 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC2919388?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000794 https://doaj.org/article/c82cebf4ac364fa59487e8aa18574021 PLoS Neglected Tropical Diseases, Vol 4, Iss 8, p e794 (2010) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2010 ftdoajarticles https://doi.org/10.1371/journal.pntd.0000794 2022-12-31T13:43:46Z 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.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.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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 4 8 e794 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Lisa Sharling Xiaoping Liu Deviprasad R Gollapalli Sushil K Maurya Lizbeth Hedstrom Boris Striepen A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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.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.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. |
format |
Article in Journal/Newspaper |
author |
Lisa Sharling Xiaoping Liu Deviprasad R Gollapalli Sushil K Maurya Lizbeth Hedstrom Boris Striepen |
author_facet |
Lisa Sharling Xiaoping Liu Deviprasad R Gollapalli Sushil K Maurya Lizbeth Hedstrom Boris Striepen |
author_sort |
Lisa Sharling |
title |
A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase. |
title_short |
A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase. |
title_full |
A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase. |
title_fullStr |
A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase. |
title_full_unstemmed |
A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase. |
title_sort |
screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2010 |
url |
https://doi.org/10.1371/journal.pntd.0000794 https://doaj.org/article/c82cebf4ac364fa59487e8aa18574021 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 4, Iss 8, p e794 (2010) |
op_relation |
http://europepmc.org/articles/PMC2919388?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000794 https://doaj.org/article/c82cebf4ac364fa59487e8aa18574021 |
op_doi |
https://doi.org/10.1371/journal.pntd.0000794 |
container_title |
PLoS Neglected Tropical Diseases |
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4 |
container_issue |
8 |
container_start_page |
e794 |
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