Testing small molecule analogues of the Acanthocheilonema viteae immunomodulator ES-62 against clinically relevant allergens.

L Janicova,K S Bell,M M Harnett,J Rzepecka,J Doonan,C J Suckling,W Harnett,F E Lumb,D T Rodgers

doi:10.1111/pim.12322

L Janicova, K S Bell + Show 7 more

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https://doi.org/10.1111/pim.12322

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Abstract

Summary 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.

Highlights

During the past decade, there has been increasing interest in the idea that parasitic worms could be employed as novel treatments to control allergic diseases such as asthma
Successful protection has been obtained when employing individual defined parasitic worm products (reviewed in [1, 4]). One of these defined products is ES-62, a phosphorylcholine (PC)containing glycoprotein secreted by Acanthocheilonema viteae, which was shown to protect against disease development in a prophylactic version of the ovalbumin-induced airway hypersensitivity model [5, 6]
Likewise, when small molecule analogues (SMAs) 12b was administered to mice at concentrations of 0Á1 lg or 10 lg per injection, the total number of cells in bronchoalveolar lavage fluid (BALF) remained unaffected in such animals, when compared to the group of untreated mice undergoing house dust mite (HDM)-induced airway hyper-responsiveness (Figure 1b)

Summary

Introduction

There has been increasing interest in the idea that parasitic worms could be employed as novel treatments to control allergic diseases such as asthma. Successful protection has been obtained when employing individual defined parasitic worm products (reviewed in [1, 4]). One of these defined products is ES-62, a phosphorylcholine (PC)containing glycoprotein secreted by Acanthocheilonema viteae, which was shown to protect against disease development in a prophylactic version of the ovalbumin-induced airway hypersensitivity model [5, 6]. Considering ovalbumin is a protein used to model physiologically relevant allergens, we have investigated whether these SMAs are protective when administered to mice given allergens to which humans are naturally exposed, namely house dust mite (HDM) and cockroach (CR) extract

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