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- Title
To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?
- Authors
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
- Abstract
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.
- Subjects
CYCLIC nucleotide phosphodiesterases; SCHISTOSOMA mansoni; CATALYTIC domains; DRUG discovery; NEGLECTED diseases
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 7, p6817
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms24076817