Targeting an Initiator Allergen Provides Durable and Expansive Protection against House Dust Mite Allergy.
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Embargo End Date
ICR Authors
Authors
Zhang, J
Chen, J
Richardson, JP
Francis-Newton, N-J
Lai, PF
Jenkins, K
Major, MR
Key, RE
Stewart, ME
Firth-Clark, S
Lloyd, SM
Newton, GK
Perrior, TR
Garrod, DR
Robinson, C
Chen, J
Richardson, JP
Francis-Newton, N-J
Lai, PF
Jenkins, K
Major, MR
Key, RE
Stewart, ME
Firth-Clark, S
Lloyd, SM
Newton, GK
Perrior, TR
Garrod, DR
Robinson, C
Document Type
Journal Article
Date
2022-09-09
Date Accepted
2022-09-09
Abstract
Whereas treatment of allergic diseases such as asthma relies largely on the targeting of dysregulated effector pathways, the conceptually attractive alternative of preventing them by a pharmaceutical, at-source intervention has been stymied until now by uncertainties about suitable targets and the challenges facing drug design. House dust mites (HDMs) are globally significant triggers of allergy. Group 1 HDM allergens, exemplified by Der p 1, are cysteine proteases. Their degradome has a strong disease linkage that underlies their status as risk and initiator allergens acting directly and through bystander effects on other allergens. Our objective was to test whether target-selective inhibitors of group 1 HDM allergens might provide a viable route to novel therapies. Using structure-directed design to optimize a series of pyruvamides, we undertook the first examination of whether pharmaceutically developable inhibitors of group 1 allergens might offer protection against HDM exposure. Developability criteria included durable inhibition of clinically relevant signals after a single aerosolized dose of the drug. The compounds suppressed acute airway responses of rats and mice when challenged with an HDM extract representing the HDM allergome. Inhibitory effects operated through a miscellany of downstream pathways involving, among others, IL-33, thymic stromal lymphopoietin, chemokines, and dendritic cells. IL-13 and eosinophil recruitment, indices of Th2 pathway activation, were strongly attenuated. The surprisingly expansive benefits arising from a unique at-source intervention suggest a novel approach to multiple allergic diseases in which HDMs play prominent roles and encourage exploration of these pharmaceutically developable molecules in a clinical setting.
Citation
ACS pharmacology & translational science, 2022, 5 (9), pp. 735 - 751
Source Title
ACS pharmacology & translational science
Publisher
AMER CHEMICAL SOC
ISSN
2575-9108
eISSN
2575-9108
2575-9108
2575-9108
Collections
Research Team
Medicinal Chemistry 3