title: Identification and activity of inhibitors of the essential nematode-specific metalloprotease DPY-31.
abstract: Infection by parasitic nematodes is widespread in the developing world causing extensive morbidity and mortality. Furthermore, infection of animals is a global problem, with a substantial impact on food production. Here we identify small molecule inhibitors of a nematode-specific metalloprotease, DPY-31, using both known metalloprotease inhibitors and virtual screening. This strategy successfully identified several μM inhibitors of DPY-31 from both the human filarial nematode Brugia malayi, and the parasitic gastrointestinal nematode of sheep Teladorsagia circumcincta. Further studies using both free living and parasitic nematodes show that these inhibitors elicit the severe body morphology defect 'Dumpy' (Dpy; shorter and fatter), a predominantly non-viable phenotype consistent with mutants lacking the DPY-31 gene. Taken together, these results represent a start point in developing DPY-31 inhibition as a totally novel mechanism for treating infection by parasitic nematodes in humans and animals.
authors.affiliation: WestChem School of Chemistry, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: France
authors.affiliation: Institute of Biodiversity, Animal Health & Comparative Medicine, University of Glasgow, Bearsden Road, Glasgow G61 1QH, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Stepek
authors.affiliation: Institute of Structural & Molecular Biology, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR, UK.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Houston
authors.affiliation: WestChem School of Chemistry, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
authors.forename: Lewis
authors.initials: L
authors.lastname: Williams
authors.affiliation: Institute of Biodiversity, Animal Health & Comparative Medicine, University of Glasgow, Bearsden Road, Glasgow G61 1QH, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: McCormack
authors.affiliation: Institute of Structural & Molecular Biology, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR, UK.
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
authors.affiliation: Institute of Biodiversity, Animal Health & Comparative Medicine, University of Glasgow, Bearsden Road, Glasgow G61 1QH, UK.
authors.forename: Antony P
authors.initials: AP
authors.lastname: Page
mesh_terms: D000818:Animals; D001665:Binding Sites; D017178:Brugia malayi / Q000201:enzymology; D017173:Caenorhabditis elegans / Q000201:enzymology; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015801:Helminth Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism; D062105:Molecular Docking Simulation; D009348:Nematoda / Q000201:enzymology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D012756:Sheep
chemical_list: D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D011994:Recombinant Proteins; C511740:DPY-31 protein, C elegans; D045726:Metalloproteases; D008666:Metalloendopeptidases
keywords: Anthelmintic; Docking; Metalloprotease inhibitor; Nematode; Peptidomimetic