title: The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.
abstract: Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma.
authors.affiliation: Department of Medicinal Chemistry, Domainex Ltd. , 162 Cambridge Science Park, Cambridge CB4 0GH, United Kingdom.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Newton
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Perrior
authors.forename: Kerry
authors.initials: K
authors.lastname: Jenkins
authors.forename: Meriel R
authors.initials: MR
authors.lastname: Major
authors.forename: Rebekah E
authors.initials: RE
authors.lastname: Key
authors.forename: Mark R
authors.initials: MR
authors.lastname: Stewart
authors.forename: Stuart
authors.initials: S
authors.lastname: Firth-Clark
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lloyd
authors.forename: Jihui
authors.initials: J
authors.lastname: Zhang
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Francis-Newton
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Richardson
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Pei
authors.initials: P
authors.lastname: Lai
authors.forename: David R
authors.initials: DR
authors.lastname: Garrod
authors.forename: Clive
authors.initials: C
authors.lastname: Robinson
mesh_terms: D000284:Administration, Oral; D000485:Allergens / Q000276:immunology; D020816:Amino Acid Motifs; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000737:chemistry*; D060829:Arthropod Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001249:Asthma / Q000188:drug therapy*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D008970:Molecular Weight; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D039981:Pyroglyphidae / Q000276:immunology
chemical_list: D000485:Allergens; D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D010455:Peptides; D003546:Cysteine Endopeptidases; C451162:Dermatophagoides pteronyssinus antigen p 1