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Background <p>Schistosomiasis, which is caused by the parasite <i>Schistosoma mansoni</i> as well as other species of the trematode genus <i>Schistosoma</i>, 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.</p> Methods <p>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 <i>S. mansoni</i> couples and newly transformed schistosomula. This was followed by confirmation of the effects of the lead structures against adult worms.</p> Results <p>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 <i>S.&#xa0;mansoni</i> but no further morphological changes. The EC<sub>50</sub>values of both compounds were determined, with values for compound OGHL00022 of 5.955&#xa0;µM for pairing stability, 10.88&#xa0;µM for attachment, and 18.77&#xa0;µM for motility, while the values for compound OGHL00121 were 7.088&#xa0;µM for pairing stability, 8.065&#xa0;µM for attachment, and 6.297&#xa0;µM for motility 24&#xa0;h after treatment. Furthermore, <i>S. mansoni</i> 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.</p> Conclusions <p>In two independent in vitro screening approaches against two stages of <i>S. mansoni</i> one common interesting structure with rapid effects was identified, OGHL00022, which provides opportunities for further development.</p> Graphical Abstract <p></p>

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Merck Open Global Health Library in vitro screening against Schistosoma mansoni identified two new substances with antischistosomal activities for further development

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月4日

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  • Monique Evelyn Ueberall,
  • Martina Berchthold,
  • Cécile Häberli,
  • Sven Lindemann,
  • Thomas Spangenberg,
  • Jennifer Keiser,
  • Christoph G. Grevelding

摘要

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