Merck Open Global Health Library in vitro screening against Schistosoma mansoni identified two new substances with antischistosomal activities for further development
Abstract Background Schistosomiasis, which is caused by the parasite Schistosoma mansoni as well as other species of the trematode genus Schistosoma, leads to chronic inflammation and finally to liver fibrosis. If untreated, the disease can cause life-threatening complications. The current treatment...
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BMC
2025-02-01
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| Series: | Parasites & Vectors |
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| Online Access: | https://doi.org/10.1186/s13071-024-06648-0 |
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| author | Monique Evelyn Ueberall Martina Berchthold Cécile Häberli Sven Lindemann Thomas Spangenberg Jennifer Keiser Christoph G. Grevelding |
| author_facet | Monique Evelyn Ueberall Martina Berchthold Cécile Häberli Sven Lindemann Thomas Spangenberg Jennifer Keiser Christoph G. Grevelding |
| author_sort | Monique Evelyn Ueberall |
| collection | DOAJ |
| description | Abstract Background Schistosomiasis, which is caused by the parasite Schistosoma mansoni as well as other species of the trematode genus Schistosoma, leads to chronic inflammation and finally to liver fibrosis. If untreated, the disease can cause life-threatening complications. The current treatment of schistosomiasis relies on a single drug, praziquantel (PZQ). However, there is increasing concern about emerging resistance to PZQ due to its frequent use. Methods To identify potential alternative drugs for repurposing, the Open Global Health Library (OGHL) was screened in vitro, using two different screening workflows at two institutions, against adult S. mansoni couples and newly transformed schistosomula. This was followed by confirmation of the effects of the lead structures against adult worms. Results In vitro screening at one of the institutions identified two fast-acting substances affecting worm physiology (OGHL00022, OGHL00121). The effects of the two lead structures were investigated in more detail by confocal laser scanning microscopy and 5-ethynyl 2´-deoxyuridine (EdU) assays to assess morphological effects and stem cell effects. Both substances showed negative effects on stem cell proliferation in S. mansoni but no further morphological changes. The EC50values of both compounds were determined, with values for compound OGHL00022 of 5.955 µM for pairing stability, 10.88 µM for attachment, and 18.77 µM for motility, while the values for compound OGHL00121 were 7.088 µM for pairing stability, 8.065 µM for attachment, and 6.297 µM for motility 24 h after treatment. Furthermore, S. mansoni couples were treated in vitro with these two lead structures simultaneously to check for additive effects, which were found with respect to reduced motility. The second in vitro screening, primarily against newly transformed schistosomula and secondarily against adult worms, identified four lead structures in total (OGHL00006, OGHL00022, OGHL00169, OGHL00217). In addition, one of the tested analogues of the hits OGHL00006, OGHL00169, and OGHL00217 showed effects on both stages. Conclusions In two independent in vitro screening approaches against two stages of S. mansoni one common interesting structure with rapid effects was identified, OGHL00022, which provides opportunities for further development. Graphical Abstract |
| format | Article |
| id | doaj-art-0c879fb51e334d629fdca11090694c6e |
| institution | Kabale University |
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| publishDate | 2025-02-01 |
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| spelling | doaj-art-0c879fb51e334d629fdca11090694c6e2025-02-09T12:15:17ZengBMCParasites & Vectors1756-33052025-02-0118112010.1186/s13071-024-06648-0Merck Open Global Health Library in vitro screening against Schistosoma mansoni identified two new substances with antischistosomal activities for further developmentMonique Evelyn Ueberall0Martina Berchthold1Cécile Häberli2Sven Lindemann3Thomas Spangenberg4Jennifer Keiser5Christoph G. Grevelding6Institute of Parasitology, BFS, Justus Liebig University GiessenDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health InstituteDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health InstituteMerck Healthcare KgaAGlobal Health R&D of the healthcare business of Merck KGaA, Darmstadt, Germany, Ares Trading S.A., (an affiliate of Merck KGaA, Darmstadt, Germany, Route de Crassier 1Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health InstituteInstitute of Parasitology, BFS, Justus Liebig University GiessenAbstract Background Schistosomiasis, which is caused by the parasite Schistosoma mansoni as well as other species of the trematode genus Schistosoma, leads to chronic inflammation and finally to liver fibrosis. If untreated, the disease can cause life-threatening complications. The current treatment of schistosomiasis relies on a single drug, praziquantel (PZQ). However, there is increasing concern about emerging resistance to PZQ due to its frequent use. Methods To identify potential alternative drugs for repurposing, the Open Global Health Library (OGHL) was screened in vitro, using two different screening workflows at two institutions, against adult S. mansoni couples and newly transformed schistosomula. This was followed by confirmation of the effects of the lead structures against adult worms. Results In vitro screening at one of the institutions identified two fast-acting substances affecting worm physiology (OGHL00022, OGHL00121). The effects of the two lead structures were investigated in more detail by confocal laser scanning microscopy and 5-ethynyl 2´-deoxyuridine (EdU) assays to assess morphological effects and stem cell effects. Both substances showed negative effects on stem cell proliferation in S. mansoni but no further morphological changes. The EC50values of both compounds were determined, with values for compound OGHL00022 of 5.955 µM for pairing stability, 10.88 µM for attachment, and 18.77 µM for motility, while the values for compound OGHL00121 were 7.088 µM for pairing stability, 8.065 µM for attachment, and 6.297 µM for motility 24 h after treatment. Furthermore, S. mansoni couples were treated in vitro with these two lead structures simultaneously to check for additive effects, which were found with respect to reduced motility. The second in vitro screening, primarily against newly transformed schistosomula and secondarily against adult worms, identified four lead structures in total (OGHL00006, OGHL00022, OGHL00169, OGHL00217). In addition, one of the tested analogues of the hits OGHL00006, OGHL00169, and OGHL00217 showed effects on both stages. Conclusions In two independent in vitro screening approaches against two stages of S. mansoni one common interesting structure with rapid effects was identified, OGHL00022, which provides opportunities for further development. Graphical Abstracthttps://doi.org/10.1186/s13071-024-06648-0Schistosoma mansoniSchistosomiasisNeglected tropical diseaseOpen Global Health LibraryIn vitro culture |
| spellingShingle | Monique Evelyn Ueberall Martina Berchthold Cécile Häberli Sven Lindemann Thomas Spangenberg Jennifer Keiser Christoph G. Grevelding Merck Open Global Health Library in vitro screening against Schistosoma mansoni identified two new substances with antischistosomal activities for further development Parasites & Vectors Schistosoma mansoni Schistosomiasis Neglected tropical disease Open Global Health Library In vitro culture |
| title | Merck Open Global Health Library in vitro screening against Schistosoma mansoni identified two new substances with antischistosomal activities for further development |
| title_full | Merck Open Global Health Library in vitro screening against Schistosoma mansoni identified two new substances with antischistosomal activities for further development |
| title_fullStr | Merck Open Global Health Library in vitro screening against Schistosoma mansoni identified two new substances with antischistosomal activities for further development |
| title_full_unstemmed | Merck Open Global Health Library in vitro screening against Schistosoma mansoni identified two new substances with antischistosomal activities for further development |
| title_short | Merck Open Global Health Library in vitro screening against Schistosoma mansoni identified two new substances with antischistosomal activities for further development |
| title_sort | merck open global health library in vitro screening against schistosoma mansoni identified two new substances with antischistosomal activities for further development |
| topic | Schistosoma mansoni Schistosomiasis Neglected tropical disease Open Global Health Library In vitro culture |
| url | https://doi.org/10.1186/s13071-024-06648-0 |
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