Demonstration of the anthelmintic potency of marimastat in the Heligmosomoides polygyrus rodent model

Robertson, E., Harcus, Y., Johnston, C. J.C., Page, A. P. , Walkinshaw, M. D., Maizels, R. M. and Houston, D. (2018) Demonstration of the anthelmintic potency of marimastat in the Heligmosomoides polygyrus rodent model. Journal of Parasitology, 104(6), pp. 705-709. (doi:10.1645/18-33) (PMID:30085900)

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Abstract

In the course of a structure based drug discovery program the known anticancer candidate marimastat was uncovered as a potent inhibitor of an enzyme in nematode cuticle biogenesis. It was shown to kill Caenorhabditis elegans, and the sheep parasites Haemonchus contortus and Teladorsagia circumcinta via an entirely novel nematode-specific pathway, specifically by inhibiting cuticle-remodelling enzymes that the parasites require for the developmentally essential moulting process. This discovery prompted an investigation of the compound's effect on Heligmosomoides polygyrus parasites in a mouse model of helminth infection. Mice were administered the drug via oral gavage daily from day of infection for a period of 2 wk. A second group received the drug via intra-peritoneal implantation of an osmotic minipump for 4 wk. Control groups were administered identical volumes of water by oral gavage in both cases. Counts of H. polygyrus faecal egg and larval load showed that marimastat effected a consistent and significant reduction in egg laying, and a consistent but minor reduction in adult worm load when administered every day, starting on the first day of infection. However, the drug failed to have any significant effect on egg counts or worm burdens when administered to mice with established infections. Therefore, marimastat does not appear to show promise as an anthelmintic in gastrointestinal nematode infections, although other metalloproteases such as batimastat may prove more effective.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Page, Professor Tony and Maizels, Professor Rick
Authors: Robertson, E., Harcus, Y., Johnston, C. J.C., Page, A. P., Walkinshaw, M. D., Maizels, R. M., and Houston, D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Parasitology
Publisher:American Society of Parasitologists
ISSN:0022-3395
ISSN (Online):1937-2345
Published Online:29 August 2018
Copyright Holders:Copyright © 2018 American Society of Parasitologists
First Published:First published in Journal of Parasitology 104(6): 705-709
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
765221Helminths and the Immune System: Regulation, Regulators and ImmunityRichard MaizelsWellcome Trust (WELLCOTR)106122/A/14/ZIII - PARASITOLOGY
371799The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/Z & AIII - PARASITOLOGY
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