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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)5752-5755
Number of pages4
JournalBioorganic & Medicinal Chemistry Letters
Volume25
Issue number24
Early online date3 Nov 2015
DOIs
Publication statusPublished - 15 Dec 2015

Keywords

  • Anthelmintic
  • Docking
  • Metalloprotease inhibitor
  • Nematode
  • Peptidomimetic

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