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)

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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:Page, Professor Tony and McCormack, Ms Gillian and Stepek, Dr Gillian and France, Dr David
Authors: France, D. J., Stepek, G., Houston, D. R., Williams, L., McCormack, G., Walkinshaw, M. D., and Page, A. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Science and Engineering > School of Chemistry
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

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
543261The matrix associated astacin enzymes; novel targets in the control of key GI nematodes of ruminants.Antony PageBiotechnology and Biological Sciences Research Council (BBSRC)BB/I011218/1III - PARASITOLOGY