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

Theodor Bilharz Research Institute

Bibliographic Information

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.; de Koning H.P.

Journal: PLoS Neglected Tropical Diseases

Publisher: Public Library of Science

Publication Date: 30 July 2020

Volume / Issue: Volume 14 / Issue 7

Pages: 1–29

Article No.: e0008447

ISSN: 19352727

DOI: 10.1371/journal.pntd.0008447

Scopus: View on Scopus

PubMed: 32730343

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Munday J.C., Institute of Infection, Immunity and inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom; Kunz S., Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Netherlands; Kalejaiye T.D., Institute of Infection, Immunity and inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom; Siderius M., Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Netherlands; Schroeder S., School of Biosciences, University of Kent, United Kingdom; Paape D., Institute of Infection, Immunity and inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom; Alghamdi A.H., Institute of Infection, Immunity and inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom; Abbasi Z., Biology Department, Boston College, Chestnut Hill, MA, United States; Huang S.X., Biology Department, Boston College, Chestnut Hill, MA, United States; Donachie A.-M., Institute of Infection, Immunity and inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom; William S., Department of Pharmacology, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, Egypt; Sabra A.N., Department of Pharmacology, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, Egypt; Sterk G.J., Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Netherlands; Botros S.S., Department of Pharmacology, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, Egypt; Brown D.G., School of Biosciences, University of Kent, United Kingdom; Hoffman C.S., Biology Department, Boston College, Chestnut Hill, MA, United States; Leurs R., Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Netherlands; de Koning H.P., Institute of Infection, Immunity and inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom

Abstract

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. How-ever, regulatory systems including cyclic nucleotide metabolism are emerging as primary candidates for drug discovery. Here, we report the cloning of ten cyclic nucleotide phospho-diesterase (PDE) genes of S. mansoni, out of a total of 11 identified in its genome. We clas-sify 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. © 2020 Munday et al.

Keywords

Animals; Cell Line; Cloning, Molecular; Gene Deletion; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Genome, Helminth; Helminth Proteins; Male; Mice; Phosphoric Diester Hydrolases; Phylogeny; Schistosoma mansoni; Trypanosoma brucei brucei; Yeasts; complementary DNA; cyclic AMP; cyclic GMP; cyclic nucleotide phosphodiesterase; genomic DNA; phosphodiesterase; helminth protein; adult; amino terminal sequence; Article; bacterial strain; Caenorhabditis elegans; carboxy terminal sequence; cloning; Drosophila melanogaster; female; fluorescence imaging; fungal strain; gene; gene amplification; gene expression level; gene frequency; gene identification; gene sequence; genetic transfection; immunofluorescence test; immunolocalization; nonhuman; real time polymerase chain reaction; Saccharomyces cerevisiae; Schizosaccharomyces pombe; SmPDE1 gene; SmPDE11 gene; SmPDE4A gene; SmPDE8 gene; SmPDE9A gene; Trypanosoma brucei; animal; enzymology; gene expression regulation; genetics; genome; metabolism; molecular cloning; mouse; physiology; yeast

Citation Information

Scopus Citations: 3

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