Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium.
Background Anthelminthic treatment options against schistosomiasis are limited. The current treatment relies almost exclusively on a single drug, praziquantel (PZQ). As a consequence, the development of resistance to PZQ and limited activity of PZQ against earlier development stages are respectively...
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ftdoajarticles:oai:doaj.org/article:12d9676546434831be89218d4d3f8d96 2023-05-15T15:16:20+02:00 Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium. Nermina Vejzagić Ulrich Fabien Prodjinotho Nagwa El-Khafif Ruili Huang Anton Simeonov Thomas Spangenberg Clarissa Prazeres da Costa 2021-05-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0009432 https://doaj.org/article/12d9676546434831be89218d4d3f8d96 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0009432 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009432 https://doaj.org/article/12d9676546434831be89218d4d3f8d96 PLoS Neglected Tropical Diseases, Vol 15, Iss 5, p e0009432 (2021) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles https://doi.org/10.1371/journal.pntd.0009432 2022-12-31T11:01:42Z Background Anthelminthic treatment options against schistosomiasis are limited. The current treatment relies almost exclusively on a single drug, praziquantel (PZQ). As a consequence, the development of resistance to PZQ and limited activity of PZQ against earlier development stages are respectively a risk and a limitation to achieving the goals of the new WHO roadmap towards elimination. For the discovery of new chemical starting points, the in vitro drug screening on Schistosoma mansoni (S. mansoni) against newly transformed schistosomula (NTS) is still the most predominant approach. The use of only NTS in the initial screening limits sensitivity to potential new compounds which are predominantly active in later developmental stages. Using our recently described highly standardized, straightforward and reliable culture method that generates high rates of juvenile worms, we aimed to repurpose a subset of the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection (340 compounds) to identify new hits with an in vitro worm culture assay. Methodology/principal findings Cercariae were mechanically transformed into skin-stage (SkS) schistosomula and continuously cultured for 3-6 weeks to the liver stage (LiS). A commercial source of serum was identified, and decrease of NTS/well along with optimal drug testing conditions was established to test compounds on early and late LiS worms. The library was screened in 96-well format assays using praziquantel (PZQ) as a positive control. Primary screening allowed a 5.9% hit rate and generated two confirmed hits on adult worms; a prophylactic antianginal agent and an antihistaminic drug. Conclusion With this standardized and reliable in vitro assay, important S. mansoni developmental stages up to LiS worms can be generated and cultured over an extended period. When exposed to a subset of the NCATS Pharmaceutical Collection, 3 compounds yielded a defined anti-schistosomal phenotype on juvenile worms. Translation of activity on perfused adult S. ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 15 5 e0009432 |
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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 Nermina Vejzagić Ulrich Fabien Prodjinotho Nagwa El-Khafif Ruili Huang Anton Simeonov Thomas Spangenberg Clarissa Prazeres da Costa Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Background Anthelminthic treatment options against schistosomiasis are limited. The current treatment relies almost exclusively on a single drug, praziquantel (PZQ). As a consequence, the development of resistance to PZQ and limited activity of PZQ against earlier development stages are respectively a risk and a limitation to achieving the goals of the new WHO roadmap towards elimination. For the discovery of new chemical starting points, the in vitro drug screening on Schistosoma mansoni (S. mansoni) against newly transformed schistosomula (NTS) is still the most predominant approach. The use of only NTS in the initial screening limits sensitivity to potential new compounds which are predominantly active in later developmental stages. Using our recently described highly standardized, straightforward and reliable culture method that generates high rates of juvenile worms, we aimed to repurpose a subset of the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection (340 compounds) to identify new hits with an in vitro worm culture assay. Methodology/principal findings Cercariae were mechanically transformed into skin-stage (SkS) schistosomula and continuously cultured for 3-6 weeks to the liver stage (LiS). A commercial source of serum was identified, and decrease of NTS/well along with optimal drug testing conditions was established to test compounds on early and late LiS worms. The library was screened in 96-well format assays using praziquantel (PZQ) as a positive control. Primary screening allowed a 5.9% hit rate and generated two confirmed hits on adult worms; a prophylactic antianginal agent and an antihistaminic drug. Conclusion With this standardized and reliable in vitro assay, important S. mansoni developmental stages up to LiS worms can be generated and cultured over an extended period. When exposed to a subset of the NCATS Pharmaceutical Collection, 3 compounds yielded a defined anti-schistosomal phenotype on juvenile worms. Translation of activity on perfused adult S. ... |
format |
Article in Journal/Newspaper |
author |
Nermina Vejzagić Ulrich Fabien Prodjinotho Nagwa El-Khafif Ruili Huang Anton Simeonov Thomas Spangenberg Clarissa Prazeres da Costa |
author_facet |
Nermina Vejzagić Ulrich Fabien Prodjinotho Nagwa El-Khafif Ruili Huang Anton Simeonov Thomas Spangenberg Clarissa Prazeres da Costa |
author_sort |
Nermina Vejzagić |
title |
Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium. |
title_short |
Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium. |
title_full |
Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium. |
title_fullStr |
Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium. |
title_full_unstemmed |
Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium. |
title_sort |
identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2021 |
url |
https://doi.org/10.1371/journal.pntd.0009432 https://doaj.org/article/12d9676546434831be89218d4d3f8d96 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 15, Iss 5, p e0009432 (2021) |
op_relation |
https://doi.org/10.1371/journal.pntd.0009432 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009432 https://doaj.org/article/12d9676546434831be89218d4d3f8d96 |
op_doi |
https://doi.org/10.1371/journal.pntd.0009432 |
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PLOS Neglected Tropical Diseases |
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15 |
container_issue |
5 |
container_start_page |
e0009432 |
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1766346624296026112 |