Identification and activity of inhibitors of the essential nematode-specific metalloprotease DPY-31. Issue 24 (15th December 2015)

• Record Type: Journal Article
• Authors: France, David J.; Stepek, Gillian; Houston, Douglas R.; Williams, Lewis; McCormack, Gillian; Walkinshaw, Malcolm D.; Page, Antony P.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 24(2015)
• Page Start: 5752
• Page End: 5755
• Publication Date: 2015-12-15
• Subjects: Nematode -- Anthelmintic -- Metalloprotease inhibitor -- Docking -- Peptidomimetic; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.10.077
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.