Testing small molecule analogues of theAcanthocheilonema viteaeimmunomodulator ES-62 against clinically relevant allergens

Janicova, L., Rzepecka, J., Rodgers, D.T., Doonan, J., Bell, K.S., Lumb, F.E., Suckling, C.J., Harnett, M.M. and Harnett, W. (2016) Testing small molecule analogues of theAcanthocheilonema viteaeimmunomodulator ES-62 against clinically relevant allergens. Parasite Immunology, 38(6), pp. 340-351. (doi:10.1111/pim.12322) (PMID:27059010) (PMCID:PMC4913752)

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Abstract

ES-62 is a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae that protects against ovalbumin (OVA)-induced airway hyper-responsiveness in mice by virtue of covalently attached anti-inflammatory phosphorylcholine (PC) residues. We have recently generated a library of small molecule analogues (SMAs) of ES-62 based around its active PC moiety as a starting point in novel drug development for asthma and identified two compounds – termed 11a and 12b – that mirror ES-62's protective effects. In this study, we have moved away from OVA, a model allergen, to test the SMAs against two clinically relevant allergens – house dust mite (HDM) and cockroach allergen (CR) extract. We show that both SMAs offer some protection against development of lung allergic responses to CR, in particular reducing eosinophil infiltration, whereas only SMA 12b is effective in protecting against eosinophil-dependent HDM-induced allergy. These data therefore suggest that helminth molecule-induced protection against model allergens may not necessarily translate to clinically relevant allergens. Nevertheless, in this study, we have managed to demonstrate that it is possible to produce synthetic drug-like molecules based on a parasitic worm product that show therapeutic potential with respect to asthma resulting from known triggers in humans.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Rodgers, Professor Dennis and Lumb, Miss Felicity and Harnett, Professor William and Doonan, Dr James
Authors: Janicova, L., Rzepecka, J., Rodgers, D.T., Doonan, J., Bell, K.S., Lumb, F.E., Suckling, C.J., Harnett, M.M., and Harnett, W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Social Sciences > School of Social and Political Sciences
Journal Name:Parasite Immunology
Publisher:Wiley
ISSN:0141-9838
ISSN (Online):1365-3024
Published Online:30 May 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Parasite Immunology 38(6): 340-351
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
455802Small molecule analogues (SMAs) of an immunomodulatory helminth product provide a novel approach to dissecting macrophage signalsMargaret HarnettBiotechnology and Biological Sciences Research Council (BBSRC)BB/E013929/1III -IMMUNOLOGY
495342ES-62, TLR4, the Mast Cell and development of novel drugs for mast cell-mediated inflammationMargaret HarnettWellcome Trust (WELLCOME)086852/Z/08/ZIII -IMMUNOLOGY
531152Application of a Parasitic Helminth Product to the Understanding and Treatment of AsthmaMargaret HarnettAmerican Asthma Foundation (ASTHMA-US)09-0125III -IMMUNOLOGY