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

Zhang, J; Chen, J; Zuo, J; Newton, GK; Stewart, MR; Perrior, TR; Garrod, DR; Robinson, C (2018) Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 19 (10). p. 3166. ISSN 1422-0067 https://doi.org/10.3390/ijms19103166
SGUL Authors: Robinson, Clive

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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.

Item Type: Article
Additional Information: © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Keywords: 0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences, Chemical Physics
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN: 1422-0067
Dates:
DateEvent
15 October 2018Published Online
5 October 2018Accepted
Projects:
Project IDFunderFunder ID
087650Wellcome Trusthttp://dx.doi.org/10.13039/100004440
URI: https://openaccess.sgul.ac.uk/id/eprint/110272
Publisher's version: https://doi.org/10.3390/ijms19103166

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