dc.contributor.author | Zhang, J | |
dc.contributor.author | Chen, J | |
dc.contributor.author | Richardson, JP | |
dc.contributor.author | Francis-Newton, N-J | |
dc.contributor.author | Lai, PF | |
dc.contributor.author | Jenkins, K | |
dc.contributor.author | Major, MR | |
dc.contributor.author | Key, RE | |
dc.contributor.author | Stewart, ME | |
dc.contributor.author | Firth-Clark, S | |
dc.contributor.author | Lloyd, SM | |
dc.contributor.author | Newton, GK | |
dc.contributor.author | Perrior, TR | |
dc.contributor.author | Garrod, DR | |
dc.contributor.author | Robinson, C | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2022-10-17T14:28:57Z | |
dc.date.available | 2022-10-17T14:28:57Z | |
dc.date.issued | 2022-09-09 | |
dc.identifier.citation | ACS pharmacology & translational science, 2022, 5 (9), pp. 735 - 751 | en_US |
dc.identifier.issn | 2575-9108 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5539 | |
dc.identifier.eissn | 2575-9108 | |
dc.identifier.eissn | 2575-9108 | |
dc.identifier.doi | 10.1021/acsptsci.2c00022 | |
dc.description.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. | |
dc.format | Electronic-eCollection | |
dc.format.extent | 735 - 751 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | AMER CHEMICAL SOC | en_US |
dc.relation.ispartof | ACS pharmacology & translational science | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Science & Technology | |
dc.subject | Life Sciences & Biomedicine | |
dc.subject | Chemistry, Medicinal | |
dc.subject | Pharmacology & Pharmacy | |
dc.subject | house dust mite allergome | |
dc.subject | protease inhibitor | |
dc.subject | allergen | |
dc.subject | airway inflammation | |
dc.subject | eosinophil | |
dc.subject | Der p 1 | |
dc.subject | INNATE LYMPHOID-CELLS | |
dc.subject | ASTHMA | |
dc.subject | AIRWAY | |
dc.subject | GLUTATHIONE | |
dc.subject | DER-P-1 | |
dc.subject | MEDIATORS | |
dc.subject | POTENT | |
dc.subject | GENES | |
dc.subject | FLUID | |
dc.subject | IL-25 | |
dc.title | Targeting an Initiator Allergen Provides Durable and Expansive Protection against House Dust Mite Allergy. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2022-09-09 | |
dc.date.updated | 2022-10-17T14:27:28Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1021/acsptsci.2c00022 | en_US |
rioxxterms.licenseref.startdate | 2022-09-09 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/36110379 | |
pubs.issue | 9 | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3 | |
pubs.publication-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1021/acsptsci.2c00022 | |
pubs.volume | 5 | |
icr.researchteam | Medicinal Chemistry 3 | en_US |
dc.contributor.icrauthor | Newton, Gary | |
icr.provenance | Deposited by Mr Arek Surman on 2022-10-17. Deposit type is initial. No. of files: 1. Files: acsptsci.2c00022.pdf | |