Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening.
Background Praziquantel (PZQ) is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism) screening with adul...
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ftdoajarticles:oai:doaj.org/article:e07426d1155142edb442dafbc6846ea9 2023-05-15T15:15:33+02:00 Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. Maha-Hamadien Abdulla Debbie S Ruelas Brian Wolff June Snedecor Kee-Chong Lim Fengyun Xu Adam R Renslo Janice Williams James H McKerrow Conor R Caffrey 2009-07-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0000478 https://doaj.org/article/e07426d1155142edb442dafbc6846ea9 EN eng Public Library of Science (PLoS) https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19597541/?tool=EBI https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000478 https://doaj.org/article/e07426d1155142edb442dafbc6846ea9 PLoS Neglected Tropical Diseases, Vol 3, Iss 7, p e478 (2009) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2009 ftdoajarticles https://doi.org/10.1371/journal.pntd.0000478 2022-12-31T09:08:25Z Background Praziquantel (PZQ) is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism) screening with adult worms in vitro and/or animal models of disease-tools that limit automation and throughput with modern microtiter plate-formatted compound libraries. Methods A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomular stage of the parasite adapted to a 96-well plate format with a throughput of 640 compounds per month. Hits that arise are subsequently screened in vitro against adult parasites and finally for efficacy in a murine model of disease. Two GO/NO GO criteria filters in the workflow prioritize hit compounds for tests in the animal disease model in accordance with a target drug profile that demands short-course oral therapy. The screen workflow was inaugurated with 2,160 chemically diverse natural and synthetic compounds, of which 821 are drugs already approved for human use. This affords a unique starting point to 'reposition' (re-profile) drugs as anti-schistosomals with potential savings in development timelines and costs. Findings Multiple and dynamic phenotypes could be categorized for schistosomula and adults in vitro, and a diverse set of 'hit' drugs and chemistries were identified, including anti-schistosomals, anthelmintics, antibiotics, and neuromodulators. Of those hits prioritized for tests in the animal disease model, a number of leads were identified, one of which compares reasonably well with PZQ in significantly decreasing worm and egg burdens, and disease-associated pathology. Data arising from the three components of the screen are posted online as a community resource. Conclusions To accelerate the identification of novel anti-schistosomals, we have developed a partially automated screen workflow that interfaces schistosomula ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 3 7 e478 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
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English |
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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 Maha-Hamadien Abdulla Debbie S Ruelas Brian Wolff June Snedecor Kee-Chong Lim Fengyun Xu Adam R Renslo Janice Williams James H McKerrow Conor R Caffrey Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Background Praziquantel (PZQ) is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism) screening with adult worms in vitro and/or animal models of disease-tools that limit automation and throughput with modern microtiter plate-formatted compound libraries. Methods A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomular stage of the parasite adapted to a 96-well plate format with a throughput of 640 compounds per month. Hits that arise are subsequently screened in vitro against adult parasites and finally for efficacy in a murine model of disease. Two GO/NO GO criteria filters in the workflow prioritize hit compounds for tests in the animal disease model in accordance with a target drug profile that demands short-course oral therapy. The screen workflow was inaugurated with 2,160 chemically diverse natural and synthetic compounds, of which 821 are drugs already approved for human use. This affords a unique starting point to 'reposition' (re-profile) drugs as anti-schistosomals with potential savings in development timelines and costs. Findings Multiple and dynamic phenotypes could be categorized for schistosomula and adults in vitro, and a diverse set of 'hit' drugs and chemistries were identified, including anti-schistosomals, anthelmintics, antibiotics, and neuromodulators. Of those hits prioritized for tests in the animal disease model, a number of leads were identified, one of which compares reasonably well with PZQ in significantly decreasing worm and egg burdens, and disease-associated pathology. Data arising from the three components of the screen are posted online as a community resource. Conclusions To accelerate the identification of novel anti-schistosomals, we have developed a partially automated screen workflow that interfaces schistosomula ... |
format |
Article in Journal/Newspaper |
author |
Maha-Hamadien Abdulla Debbie S Ruelas Brian Wolff June Snedecor Kee-Chong Lim Fengyun Xu Adam R Renslo Janice Williams James H McKerrow Conor R Caffrey |
author_facet |
Maha-Hamadien Abdulla Debbie S Ruelas Brian Wolff June Snedecor Kee-Chong Lim Fengyun Xu Adam R Renslo Janice Williams James H McKerrow Conor R Caffrey |
author_sort |
Maha-Hamadien Abdulla |
title |
Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. |
title_short |
Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. |
title_full |
Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. |
title_fullStr |
Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. |
title_full_unstemmed |
Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. |
title_sort |
drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2009 |
url |
https://doi.org/10.1371/journal.pntd.0000478 https://doaj.org/article/e07426d1155142edb442dafbc6846ea9 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 3, Iss 7, p e478 (2009) |
op_relation |
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19597541/?tool=EBI https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000478 https://doaj.org/article/e07426d1155142edb442dafbc6846ea9 |
op_doi |
https://doi.org/10.1371/journal.pntd.0000478 |
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PLoS Neglected Tropical Diseases |
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3 |
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7 |
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e478 |
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