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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

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 funct...

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Autores principales: Zhang, Jihui, Chen, Jie, Zuo, Jie, Newton, Gary K., Stewart, Mark R., Perrior, Trevor R., Garrod, David R., Robinson, Clive
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214017/
https://www.ncbi.nlm.nih.gov/pubmed/30326568
http://dx.doi.org/10.3390/ijms19103166
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author Zhang, Jihui
Chen, Jie
Zuo, Jie
Newton, Gary K.
Stewart, Mark R.
Perrior, Trevor R.
Garrod, David R.
Robinson, Clive
author_facet Zhang, Jihui
Chen, Jie
Zuo, Jie
Newton, Gary K.
Stewart, Mark R.
Perrior, Trevor R.
Garrod, David R.
Robinson, Clive
author_sort Zhang, Jihui
collection PubMed
description 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.
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spelling pubmed-62140172018-11-14 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, Jihui Chen, Jie Zuo, Jie Newton, Gary K. Stewart, Mark R. Perrior, Trevor R. Garrod, David R. Robinson, Clive Int J Mol Sci Article 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. MDPI 2018-10-15 /pmc/articles/PMC6214017/ /pubmed/30326568 http://dx.doi.org/10.3390/ijms19103166 Text en © 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/).
spellingShingle Article
Zhang, Jihui
Chen, Jie
Zuo, Jie
Newton, Gary K.
Stewart, Mark R.
Perrior, Trevor R.
Garrod, David R.
Robinson, Clive
Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens
title Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens
title_full Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens
title_fullStr Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens
title_full_unstemmed Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens
title_short Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens
title_sort allergen delivery inhibitors: characterisation of potent and selective inhibitors of der p 1 and their attenuation of airway responses to house dust mite allergens
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214017/
https://www.ncbi.nlm.nih.gov/pubmed/30326568
http://dx.doi.org/10.3390/ijms19103166
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