A drug repurposing screen for whipworms informed by comparative genomics.
Hundreds of millions of people worldwide are infected with the whipworm Trichuris trichiura. Novel treatments are urgently needed as current drugs, such as albendazole, have relatively low efficacy. We have investigated whether drugs approved for other human diseases could be repurposed as novel ant...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-09-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0011205&type=printable |
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| author | Avril Coghlan Frederick A Partridge María Adelaida Duque-Correa Gabriel Rinaldi Simon Clare Lisa Seymour Cordelia Brandt Tapoka T Mkandawire Catherine McCarthy Nancy Holroyd Marina Nick Anwen E Brown Sirapat Tonitiwong David B Sattelle Matthew Berriman |
| author_facet | Avril Coghlan Frederick A Partridge María Adelaida Duque-Correa Gabriel Rinaldi Simon Clare Lisa Seymour Cordelia Brandt Tapoka T Mkandawire Catherine McCarthy Nancy Holroyd Marina Nick Anwen E Brown Sirapat Tonitiwong David B Sattelle Matthew Berriman |
| author_sort | Avril Coghlan |
| collection | DOAJ |
| description | Hundreds of millions of people worldwide are infected with the whipworm Trichuris trichiura. Novel treatments are urgently needed as current drugs, such as albendazole, have relatively low efficacy. We have investigated whether drugs approved for other human diseases could be repurposed as novel anti-whipworm drugs. In a previous comparative genomics analysis, we identified 409 drugs approved for human use that we predicted to target parasitic worm proteins. Here we tested these ex vivo by assessing motility of adult worms of Trichuris muris, the murine whipworm, an established model for human whipworm research. We identified 14 compounds with EC50 values of ≤50 μM against T. muris ex vivo, and selected nine for testing in vivo. However, the best worm burden reduction seen in mice was just 19%. The high number of ex vivo hits against T. muris shows that we were successful at predicting parasite proteins that could be targeted by approved drugs. In contrast, the low efficacy of these compounds in mice suggest challenges due to their chemical properties (e.g. lipophilicity, polarity, molecular weight) and pharmacokinetics (e.g. absorption, distribution, metabolism, and excretion) that may (i) promote absorption by the host gastrointestinal tract, thereby reducing availability to the worms embedded in the large intestine, and/or (ii) restrict drug uptake by the worms. This indicates that identifying structural analogues that have reduced absorption by the host, and increased uptake by worms, may be necessary for successful drug development against whipworms. |
| format | Article |
| id | doaj-art-a9399883925e4c239ce6cfe85ef5286d |
| institution | Kabale University |
| issn | 1935-2727 1935-2735 |
| language | English |
| publishDate | 2023-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj-art-a9399883925e4c239ce6cfe85ef5286d2025-08-20T03:47:05ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352023-09-01179e001120510.1371/journal.pntd.0011205A drug repurposing screen for whipworms informed by comparative genomics.Avril CoghlanFrederick A PartridgeMaría Adelaida Duque-CorreaGabriel RinaldiSimon ClareLisa SeymourCordelia BrandtTapoka T MkandawireCatherine McCarthyNancy HolroydMarina NickAnwen E BrownSirapat TonitiwongDavid B SattelleMatthew BerrimanHundreds of millions of people worldwide are infected with the whipworm Trichuris trichiura. Novel treatments are urgently needed as current drugs, such as albendazole, have relatively low efficacy. We have investigated whether drugs approved for other human diseases could be repurposed as novel anti-whipworm drugs. In a previous comparative genomics analysis, we identified 409 drugs approved for human use that we predicted to target parasitic worm proteins. Here we tested these ex vivo by assessing motility of adult worms of Trichuris muris, the murine whipworm, an established model for human whipworm research. We identified 14 compounds with EC50 values of ≤50 μM against T. muris ex vivo, and selected nine for testing in vivo. However, the best worm burden reduction seen in mice was just 19%. The high number of ex vivo hits against T. muris shows that we were successful at predicting parasite proteins that could be targeted by approved drugs. In contrast, the low efficacy of these compounds in mice suggest challenges due to their chemical properties (e.g. lipophilicity, polarity, molecular weight) and pharmacokinetics (e.g. absorption, distribution, metabolism, and excretion) that may (i) promote absorption by the host gastrointestinal tract, thereby reducing availability to the worms embedded in the large intestine, and/or (ii) restrict drug uptake by the worms. This indicates that identifying structural analogues that have reduced absorption by the host, and increased uptake by worms, may be necessary for successful drug development against whipworms.https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0011205&type=printable |
| spellingShingle | Avril Coghlan Frederick A Partridge María Adelaida Duque-Correa Gabriel Rinaldi Simon Clare Lisa Seymour Cordelia Brandt Tapoka T Mkandawire Catherine McCarthy Nancy Holroyd Marina Nick Anwen E Brown Sirapat Tonitiwong David B Sattelle Matthew Berriman A drug repurposing screen for whipworms informed by comparative genomics. PLoS Neglected Tropical Diseases |
| title | A drug repurposing screen for whipworms informed by comparative genomics. |
| title_full | A drug repurposing screen for whipworms informed by comparative genomics. |
| title_fullStr | A drug repurposing screen for whipworms informed by comparative genomics. |
| title_full_unstemmed | A drug repurposing screen for whipworms informed by comparative genomics. |
| title_short | A drug repurposing screen for whipworms informed by comparative genomics. |
| title_sort | drug repurposing screen for whipworms informed by comparative genomics |
| url | https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0011205&type=printable |
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