Academic Journal
To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?
| العنوان: | To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A? |
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| المؤلفون: | Zheng, Yang, Schroeder, Susanne, Kanev, Georgi K., Botros, Sanaa S., William, Samia, Sabra, Abdel-Nasser A., Maes, Louis, Caljon, Guy, Gil, Carmen, Martinez, Ana, Salado, Irene G., Augustyns, Koen, Edink, Ewald, Sijm, Maarten, de Heuvel, Erik, de Esch, Iwan J. P., van der Meer, Tiffany, Siderius, Marco, Sterk, Geert Jan, Brown, David G., Leurs, Rob |
| بيانات النشر: | MDPI |
| سنة النشر: | 2023 |
| المجموعة: | University of Kent: KAR - Kent Academic Repository |
| مصطلحات موضوعية: | Q Science, QH Natural history, QH301 Biology |
| الوصف: | Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | https://kar.kent.ac.uk/100907/1/D.%20Brown%20-%20to%20target%20or%20not%20to%20target%20Schistosoma%20mansoni%20Cyclic%20Nucleotide%20Phosphodiesterase%204A%20-%20PPDF.pdf; Zheng, Yang, Schroeder, Susanne, Kanev, Georgi K., Botros, Sanaa S., William, Samia, Sabra, Abdel-Nasser A., Maes, Louis, Caljon, Guy, Gil, Carmen, Martinez, Ana, and others. Salado, Irene G., Augustyns, Koen, Edink, Ewald, Sijm, Maarten, de Heuvel, Erik, de Esch, Iwan J. P., van der Meer, Tiffany, Siderius, Marco, Sterk, Geert Jan, Brown, David G., and Leurs, Rob (hide) (2023) To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A? International Journal of Molecular Sciences, 24 (7). Article Number 6817. ISSN 1422-0067. (doi:10.3390/ijms24076817 ) (KAR id:100907 ) |
| DOI: | 10.3390/ijms24076817 |
| الاتاحة: | https://kar.kent.ac.uk/100907/ https://doi.org/10.3390/ijms24076817 |
| Rights: | cc_by |
| رقم الانضمام: | edsbas.F4D51B88 |
| قاعدة البيانات: | BASE |
| DOI: | 10.3390/ijms24076817 |
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