Targeting an Initiator Allergen Provides Durable and Expansive Protection against House Dust Mite Allergy

• DOI: 10.1021/acsptsci.2c00022
• Publication Date: 2022-08-12T23:50:04Z
• Authors: Jihui Zhang; Jie Chen; Jonathan P. Richa...; Nicola-Jane Franc...; Pei F. Lai; Kerry Jenkins; Meriel R. Major; Rebekah E. Key; Mark E. Stewart; Stuart Firth-Clark; Steven M. Lloyd; Gary K. Newton; Trevor R. Perrior; David R. Garrod; Clive Robinson
• Keywords: Der p 1; 0301 basic medicine; GENES; AIRWAY; INNATE LYMPHOID-CELLS; 610; airway inflammation; Medicinal; protease inhibitor; 03 medical and health sciences; IL-25; GLUTATHIONE; eosinophil; Pharmacology & Pharmacy; house dust mite allergome; Science & Technology; POTENT; FLUID; 3. Good health; Chemistry; ASTHMA; MEDIATORS; Life Sciences & Biomedicine; DER-P-1; allergen

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.