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Int. J. Mol. Sci. 2018, 19(10), 3166; https://doi.org/10.3390/ijms19103166

Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens

1
Institute for Infection & Immunity, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK
2
State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
3
BOE Technology Center, BOE Technology Group Co., Ltd., Beijing 100176, China
4
Domainex Ltd., Chesterford Research Park, Little Chesterford, Saffron Walden, Essex CB10 1XL, UK
5
Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PL, UK
*
Author to whom correspondence should be addressed.
Received: 31 August 2018 / Revised: 5 October 2018 / Accepted: 5 October 2018 / Published: 15 October 2018
(This article belongs to the Special Issue Molecular Research on Mucosal Immunity)
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Abstract

Group 1 allergens of house dust mites (HDM) are globally significant triggers of allergic disease. They are considered as initiator allergens because their protease activity enables the development of allergy to a spectrum of unrelated allergens from various sources. This initiator-perpetuator function identifies Group 1 HDM allergens as attractive drug design targets for the first small-molecule approach directed towards a non-human, root cause trigger of allergic disease. The purpose of this study was to: (i) identify exemplar inhibitors of these allergens using Der p 1 as a design template, and (ii) characterise the pharmacological profiles of these compounds using in vitro and in vivo models relevant to allergy. Potent inhibitors representing four different chemotypes and differentiated by mechanism of action were investigated. These compounds prevented the ab initio development of allergy to the full spectrum of HDM allergens and in established allergy they inhibited the recruitment of inflammatory cells and blunted acute allergic bronchoconstriction following aerosol challenge with the full HDM allergen repertoire. Collectively, the data obtained in these experiments demonstrate that the selective pharmacological targeting of Der p 1 achieves an attractive range of benefits against exposure to all HDM allergens, consistent with the initiator-perpetuator function of this allergen. View Full-Text
Keywords: Der p 1; airway inflammation; eosinophil; house dust mite; allergens; allergen delivery inhibitor Der p 1; airway inflammation; eosinophil; house dust mite; allergens; allergen delivery inhibitor
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Zhang, J.; Chen, J.; Zuo, J.; Newton, G.K.; Stewart, M.R.; Perrior, T.R.; Garrod, D.R.; Robinson, C. Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens. Int. J. Mol. Sci. 2018, 19, 3166.

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