To Target or Not to Target ISchistosoma mansoni/I Cyclic Nucleotide Phosphodiesterase 4A?

• Published in: International journal of molecular sciences 2023-04, Vol.24 (7)
• Main Authors: Zheng, Yang, Schroeder, Susanne, Kanev, Georgi K, Botros, Sanaa S, William, Samia, Sabra, Abdel-Nasser A, Maes, Louis, Caljon, Guy, Gil, Carmen, Ma, 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, Leurs, Rob
• Format: Article
• Language: English
• Subjects: Cyclic adenylic acid; Drug discovery; Proteins; Roflumilast
• ISSN: 1422-0067
• DOI: 10.3390/ijms24076817

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.