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Allergen Delivery Inhibitors: A Rationale for Targeting Sentinel Innate Immune Signaling of Group 1 House Dust Mite Allergens through Structure-Based Protease Inhibitor Design

Diverse evidence from epidemiologic surveys and investigations into the molecular basis of allergenicity have revealed that a small cadre of “initiator” allergens promote the development of allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis. Pre-eminent among these initiator...

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Autores principales: Zhang, Jihui, Chen, Jie, Newton, Gary K., Perrior, Trevor R., Robinson, Clive
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Pharmacology and Experimental Therapeutics 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064784/
https://www.ncbi.nlm.nih.gov/pubmed/29976563
http://dx.doi.org/10.1124/mol.118.112730
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author Zhang, Jihui
Chen, Jie
Newton, Gary K.
Perrior, Trevor R.
Robinson, Clive
author_facet Zhang, Jihui
Chen, Jie
Newton, Gary K.
Perrior, Trevor R.
Robinson, Clive
author_sort Zhang, Jihui
collection PubMed
description Diverse evidence from epidemiologic surveys and investigations into the molecular basis of allergenicity have revealed that a small cadre of “initiator” allergens promote the development of allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis. Pre-eminent among these initiators are the group 1 allergens from house dust mites (HDM). In mites, group 1 allergens function as cysteine peptidase digestive enzymes to which humans are exposed by inhalation of HDM fecal pellets. Their protease nature confers the ability to activate high gain signaling mechanisms which promote innate immune responses, leading to the persistence of allergic sensitization. An important feature of this process is that the initiator drives responses both to itself and to unrelated allergens lacking these properties through a process of collateral priming. The clinical significance of group 1 HDM allergens in disease, their serodominance as allergens, and their IgE-independent bioactivities in innate immunity make these allergens interesting therapeutic targets in the design of new small-molecule interventions in allergic disease. The attraction of this new approach is that it offers a powerful, root-cause-level intervention from which beneficial effects can be anticipated by interference in a wide range of effector pathways associated with these complex diseases. This review addresses the general background to HDM allergens and the validation of group 1 as putative targets. We then discuss structure-based drug design of the first-in-class representatives of allergen delivery inhibitors aimed at neutralizing the proteolytic effects of HDM group 1 allergens, which are essential to the development and maintenance of allergic diseases.
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spelling pubmed-60647842018-09-01 Allergen Delivery Inhibitors: A Rationale for Targeting Sentinel Innate Immune Signaling of Group 1 House Dust Mite Allergens through Structure-Based Protease Inhibitor Design Zhang, Jihui Chen, Jie Newton, Gary K. Perrior, Trevor R. Robinson, Clive Mol Pharmacol Minireview Diverse evidence from epidemiologic surveys and investigations into the molecular basis of allergenicity have revealed that a small cadre of “initiator” allergens promote the development of allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis. Pre-eminent among these initiators are the group 1 allergens from house dust mites (HDM). In mites, group 1 allergens function as cysteine peptidase digestive enzymes to which humans are exposed by inhalation of HDM fecal pellets. Their protease nature confers the ability to activate high gain signaling mechanisms which promote innate immune responses, leading to the persistence of allergic sensitization. An important feature of this process is that the initiator drives responses both to itself and to unrelated allergens lacking these properties through a process of collateral priming. The clinical significance of group 1 HDM allergens in disease, their serodominance as allergens, and their IgE-independent bioactivities in innate immunity make these allergens interesting therapeutic targets in the design of new small-molecule interventions in allergic disease. The attraction of this new approach is that it offers a powerful, root-cause-level intervention from which beneficial effects can be anticipated by interference in a wide range of effector pathways associated with these complex diseases. This review addresses the general background to HDM allergens and the validation of group 1 as putative targets. We then discuss structure-based drug design of the first-in-class representatives of allergen delivery inhibitors aimed at neutralizing the proteolytic effects of HDM group 1 allergens, which are essential to the development and maintenance of allergic diseases. The American Society for Pharmacology and Experimental Therapeutics 2018-09 2018-09 /pmc/articles/PMC6064784/ /pubmed/29976563 http://dx.doi.org/10.1124/mol.118.112730 Text en Copyright © 2018 The Author(s). http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the CC BY Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Minireview
Zhang, Jihui
Chen, Jie
Newton, Gary K.
Perrior, Trevor R.
Robinson, Clive
Allergen Delivery Inhibitors: A Rationale for Targeting Sentinel Innate Immune Signaling of Group 1 House Dust Mite Allergens through Structure-Based Protease Inhibitor Design
title Allergen Delivery Inhibitors: A Rationale for Targeting Sentinel Innate Immune Signaling of Group 1 House Dust Mite Allergens through Structure-Based Protease Inhibitor Design
title_full Allergen Delivery Inhibitors: A Rationale for Targeting Sentinel Innate Immune Signaling of Group 1 House Dust Mite Allergens through Structure-Based Protease Inhibitor Design
title_fullStr Allergen Delivery Inhibitors: A Rationale for Targeting Sentinel Innate Immune Signaling of Group 1 House Dust Mite Allergens through Structure-Based Protease Inhibitor Design
title_full_unstemmed Allergen Delivery Inhibitors: A Rationale for Targeting Sentinel Innate Immune Signaling of Group 1 House Dust Mite Allergens through Structure-Based Protease Inhibitor Design
title_short Allergen Delivery Inhibitors: A Rationale for Targeting Sentinel Innate Immune Signaling of Group 1 House Dust Mite Allergens through Structure-Based Protease Inhibitor Design
title_sort allergen delivery inhibitors: a rationale for targeting sentinel innate immune signaling of group 1 house dust mite allergens through structure-based protease inhibitor design
topic Minireview
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064784/
https://www.ncbi.nlm.nih.gov/pubmed/29976563
http://dx.doi.org/10.1124/mol.118.112730
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