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dc.contributor.authorZhang, J
dc.contributor.authorChen, J
dc.contributor.authorZuo, J
dc.contributor.authorNewton, GK
dc.contributor.authorStewart, MR
dc.contributor.authorPerrior, TR
dc.contributor.authorGarrod, DR
dc.contributor.authorRobinson, C
dc.date.accessioned2020-08-13T15:38:58Z
dc.date.issued2018-10-15
dc.identifier.citationInternational journal of molecular sciences, 2018, 19 (10)
dc.identifier.issn1422-0067
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3962
dc.identifier.eissn1422-0067
dc.identifier.doi10.3390/ijms19103166
dc.description.abstractGroup 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.
dc.formatElectronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectRespiratory Mucosa
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectHypersensitivity
dc.subjectDisease Models, Animal
dc.subjectCysteine Endopeptidases
dc.subjectAnti-Allergic Agents
dc.subjectAntigens, Dermatophagoides
dc.subjectCytokines
dc.subjectRespiratory Function Tests
dc.subjectAmino Acid Sequence
dc.subjectDrug Design
dc.subjectKinetics
dc.subjectImmunomodulation
dc.subjectProteolysis
dc.subjectArthropod Proteins
dc.titleAllergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens.
dc.typeJournal Article
dcterms.dateAccepted2018-10-05
rioxxterms.versionofrecord10.3390/ijms19103166
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-10-15
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfInternational journal of molecular sciences
pubs.issue10
pubs.notesNot known
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.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-statusPublished
pubs.volume19
pubs.embargo.termsNot known
icr.researchteamMedicinal Chemistry 3en_US
dc.contributor.icrauthorNewton, Garyen


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