Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens.
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Date
2018-10-15ICR Author
Author
Zhang, J
Chen, J
Zuo, J
Newton, GK
Stewart, MR
Perrior, TR
Garrod, DR
Robinson, C
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Respiratory Mucosa
Animals
Humans
Mice
Hypersensitivity
Disease Models, Animal
Cysteine Endopeptidases
Anti-Allergic Agents
Antigens, Dermatophagoides
Cytokines
Respiratory Function Tests
Amino Acid Sequence
Drug Design
Kinetics
Immunomodulation
Proteolysis
Arthropod Proteins
Research team
Medicinal Chemistry 3
Language
eng
Date accepted
2018-10-05
License start date
2018-10-15
Citation
International journal of molecular sciences, 2018, 19 (10)
Publisher
MDPI