Cloning and functional complementation of ten Schistosoma mansoni phosphodiesterases expressed in the mammalian host stages

Munday, J. C. et al. (2020) Cloning and functional complementation of ten Schistosoma mansoni phosphodiesterases expressed in the mammalian host stages. PLoS Neglected Tropical Diseases, 14(7), e0008447. (doi: 10.1371/journal.pntd.0008447) (PMID:32730343) (PMCID:PMC7430754)

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Only a single drug against schistosomiasis is currently available and new drug development is urgently required but very few drug targets have been validated and characterised. However, regulatory systems including cyclic nucleotide metabolism are emerging as primary candidates for drug discovery. Here, we report the cloning of ten cyclic nucleotide phosphodiesterase (PDE) genes of S. mansoni, out of a total of 11 identified in its genome. We classify these PDEs by homology to human PDEs. Male worms displayed higher expression levels for all PDEs, in mature and juvenile worms, and schistosomula. Several functional complementation approaches were used to characterise these genes. We constructed a Trypanosoma brucei cell line in which expression of a cAMP-degrading PDE complements the deletion of TbrPDEB1/B2. Inhibitor screens of these cells expressing only either SmPDE4A, TbrPDEB1 or TbrPDEB2, identified highly potent inhibitors of the S. mansoni enzyme that elevated the cellular cAMP concentration. We further expressed most of the cloned SmPDEs in two pde1Δ/pde2Δ strains of Saccharomyces cerevisiae and some also in a specialised strain of Schizosacharomyces pombe. Five PDEs, SmPDE1, SmPDE4A, SmPDE8, SmPDE9A and SmPDE11 successfully complemented the S. cerevisiae strains, and SmPDE7var also complemented to a lesser degree, in liquid culture. SmPDE4A, SmPDE8 and SmPDE11 were further assessed in S. pombe for hydrolysis of cAMP and cGMP; SmPDE11 displayed considerable preferrence for cGMP over cAMP. These results and tools enable the pursuit of a rigorous drug discovery program based on inhibitors of S. mansoni PDEs.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Paape, Dr Daniel and Munday, Dr Jane and Kalejaiye, Miss Titilola and Alghamdi, Ali and De Koning, Professor Harry and Donachie, Ms Anne Marie
Creator Roles:
Munday, J. C.Formal analysis, Investigation, Methodology, Writing – original draft
Kalejaiye, T. D.Investigation
Paape, D.Investigation
Alghamdi, A. H.Investigation
Donachie, A.Investigation
de Koning, H. P.Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Writing – original draft, Writing – review and editing
Authors: Munday, J. C., Kunz, S., Kalejaiye, T. D., Siderius, M., Schroeder, S., Paape, D., Alghamdi, A. H., Abbasi, Z., Huang, S. X., Donachie, A.-M., William, S., Sabra, A. N., Sterk, G. J., Botros, S. S., Brown, D. G., Hoffman, C. S., Leurs, R., and de Koning, H. P.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:PLoS Neglected Tropical Diseases
Publisher:Public Library of Science
ISSN (Online):1935-2735
Published Online:30 July 2020
Copyright Holders:Copyright © 2020 Munday et al.
First Published:First published in PLoS Neglected Tropical Diseases 14(7): e0008447
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
169936PDE4NTD: Phosphodieasease inhibitors for the treatment of Neglected Parasitic Diseases.Harry De KoningEuropean Commission (EC)602666III - Parasitology