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

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.

Can Parasitic Worms Cure the Modern World’s Ills?

“…Finally, there is scope for more conventional drug discovery directed at targets identified by helminth action or mimicking the active moieties of helminth ES products. For example, small molecule analogues (SMAs) of the active phosphorylcholine-moiety of ES-62 exhibit (differential) efficacy in a range of models of allergic and autoimmune inflammatory disorders [54,[113][114][115] that might lead to the generation of combination drug therapies aimed at targeting particular defects in immunoregulation underpinning the lifestyle and age-associated comorbidities currently plaguing our societies.…”

Small Molecule Analogues of the parasitic worm product ES-62 interact with the TIR domain of MyD88 to inhibit pro-inflammatory signalling

“…Some of the sulfones were found to impact on cytokine output profiles in a manner similar to that of ES-62 and two in particular, 11a (also known as S3) and 12b (also known as S5) 13 , were selected for further evaluation. These have since been shown to be safe and effective when tested in CIA 13 , 16 , OAH 15 and other airway hypersensitivity models employing clinically relevant allergens 17 , the MRL/Lpr mouse model of SLE 18 and OSH 19 . Of note, the two SMAs acted at low doses (50 µg/kg), showed both prophylactic and therapeutic effects, and have recently been found to be protective in CIA when administered as DC therapy 14 .…”

The parasitic 68-mer peptide FhHDM-1 inhibits mixed granulocytic inflammation and airway hyperreactivity in experimental asthma

“…Although effective in suppressing airway inflammation and features of airway remodeling in a mouse model of ovalbumin-induced asthma, which promotes eosinophilic inflammation, synthetic small molecule analogs of this glycoprotein failed to demonstrate efficacy in clinically relevant models of allergic asthma. 6 Indeed, our data are the first to demonstrate efficacy of a parasite-derived peptide in suppressing neutrophilic inflammation in response to clinically relevant allergens. To validate our finding, we tested the efficacy of FhHDM-1 in a model of LPS-induced neutrophilic inflammation.…”