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

France, D. J. , Stepek, G., Houston, D. R., Williams, L., McCormack, G., Walkinshaw, M. D. and Page, A. P. (2015) Identification and activity of inhibitors of the essential nematode-specific metalloprotease DPY-31. Bioorganic and Medicinal Chemistry Letters, (doi: 10.1016/j.bmcl.2015.10.077) (PMID:26546217) (PMCID:PMC4658336)

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 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. 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stepek, Dr Gillian and McCormack, Ms Gillian and France, Dr David and Page, Professor Tony
• Authors: France, D. J., Stepek, G., Houston, D. R., Williams, L., McCormack, G., Walkinshaw, M. D., and Page, A. P.
• College/School: College of Science and Engineering > School of Chemistry; College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Bioorganic and Medicinal Chemistry Letters
• Publisher: Pergamon
• ISSN: 0960-894X
• ISSN (Online): 1464-3405|
• Copyright Holders: Copyright © 2015 The Authors
• First Published: First published in Bioorganic and Medicinal Chemistry Letters 2015
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
54326	1	The matrix associated astacin enzymes; novel targets in the control of key GI nematodes of ruminants.	Antony Page	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/I011218/1	III - PARASITOLOGY