Identification and activity of inhibitors of the essential nematode-specific metalloprotease DPY-31.

David J. France,Douglas R. Houston,Malcolm D. Walkinshaw,Gillian Stepek,Antony P. Page,Gillian McCormack,Lewis Williams

doi:10.1016/j.bmcl.2015.10.077

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.

Highlights

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 lM 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
The primary strategy for eliminating these infections is preventive chemotherapy by mass anthelmintic drug administration, an approach that will select for drug resistance.[1]
Resistance to anthelmintic drugs is increasing in gastrointestinal (GI) parasites of livestock, causing concern that this will occur in human parasites

Summary

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Citation for published version: France, DJ, Stepek, G, Houston, DR, Williams, L, McCormack, G, Walkinshaw, MD & Page, AP 2015, 'Identification and activity of inhibitors of the essential nematode-specific metalloprotease DPY-31', Bioorganic & Medicinal Chemistry Letters, vol 25, no.

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