To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?

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. (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)

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Official URL: https://doi.org/10.3390/ijms24076817

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.

Item Type:	Article
DOI/Identification number:	10.3390/ijms24076817
Uncontrolled keywords:	Inorganic Chemistry, Organic Chemistry, Physical and Theoretical Chemistry, Computer Science Applications, Spectroscopy, Molecular Biology, General Medicine, Catalysis
Subjects:	Q Science Q Science > QH Natural history Q Science > QH Natural history > QH301 Biology
Divisions:	Divisions > Division of Natural Sciences > Biosciences
Funders:	European Commission (https://ror.org/00k4n6c32) China Scholarship Council (https://ror.org/04atp4p48)
SWORD Depositor:	JISC Publications Router
Depositing User:	JISC Publications Router
Date Deposited:	18 Apr 2023 14:10 UTC
Last Modified:	05 Nov 2024 13:06 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/100907 (The current URI for this page, for reference purposes)

University of Kent Author Information

Schroeder, Susanne.

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CReDIT Contributor Roles:

Brown, David G..

Creator's ORCID:	https://orcid.org/0000-0003-4605-4779
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