Stepek, G., McCormack, G., Winter, A. D. and Page, A. P. (2015) A highly conserved, inhibitable astacin metalloprotease from Teladorsagia circumcincta is required for cuticle formation and nematode development. International Journal for Parasitology, 45(3), pp. 345-355. (doi: 10.1016/j.ijpara.2015.01.004) (PMID:25736599) (PMCID:PMC4406453)
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Abstract
Parasitic nematodes cause chronic, debilitating infections in both livestock and humans worldwide, and many have developed multiple resistance to the currently available anthelmintics. The protective collagenous cuticle of these parasites is required for nematode survival and its synthesis has been studied extensively in the free-living nematode, Caenorhabditis elegans. The collagen synthesis pathway is a complex, multi-step process involving numerous key enzymes, including the astacin metalloproteases. Nematode astacinsare crucial for C. elegans development, having specific roles in hatching, moulting and cuticle synthesis. NAS-35 (also called DPY-31), is a homologue of a vertebrate procollagen C-proteinase and performs a central role in cuticle formation of C. elegans as its mutation causes temperature-sensitive lethality and cuticle defects. The characterisation of DPY-31 from the ovine gastrointestinal nematode Teladorsagia circumcincta and its ability to rescue the C. elegans mutant is described. Compounds with a hydroxamate functional group have previously been shown to be potent inhibitors of procollagen C-proteinases and were therefore examined for inhibitory activity against the T. circumcincta enzyme. Phenotypic screening against T. circumcincta, Haemonchus contortus and C. elegans larval stages identified compounds that caused body morphology phenotypes consistent with the inhibition of proteases involved in cuticle collagen synthesis. These compounds correspondingly inhibited the activity of recombinant T. circumcincta DPY-31, supporting the hypothesis that this enzyme may represent a potentially novel anthelminthic drug target.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Stepek, Dr Gillian and Winter, Dr Alan and McCormack, Ms Gillian and Page, Professor Tony |
| Authors: | Stepek, G., McCormack, G., Winter, A. D., and Page, A. P. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine |
| Journal Name: | International Journal for Parasitology |
| Publisher: | Elsevier |
| ISSN: | 0020-7519 |
| ISSN (Online): | 1879-0135 |
| Copyright Holders: | Copyright © 2015 The Authors |
| First Published: | First published in International Journal for Parasitology 45(3):345-355 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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