Allergen Delivery Inhibitors: A Rationale for Targeting Sentinel Innate Immune Signaling of Group 1 House Dust Mite Allergens through Structure-Based Protease Inhibitor Design

Abstract

Diverse evidence from epidemiologic surveys and investigations into the molecular basis of allergenicity have revealed that a small cadre of “initiator” allergens promote the development of allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis. Pre-eminent among these initiators are the group 1 allergens from house dust mites (HDM). In mites, group 1 allergens function as cysteine peptidase digestive enzymes to which humans are exposed by inhalation of HDM fecal pellets. Their protease nature confers the ability to activate high gain signaling mechanisms which promote innate immune responses, leading to the persistence of allergic sensitization. An important feature of this process is that the initiator drives responses both to itself and to unrelated allergens lacking these properties through a process of collateral priming. The clinical significance of group 1 HDM allergens in disease, their serodominance as allergens, and their IgE-independent bioactivities in innate immunity make these allergens interesting therapeutic targets in the design of new small-molecule interventions in allergic disease. The attraction of this new approach is that it offers a powerful, root-cause-level intervention from which beneficial effects can be anticipated by interference in a wide range of effector pathways associated with these complex diseases. This review addresses the general background to HDM allergens and the validation of group 1 as putative targets. We then discuss structure-based drug design of the first-in-class representatives of allergen delivery inhibitors aimed at neutralizing the proteolytic effects of HDM group 1 allergens, which are essential to the development and maintenance of allergic diseases.

Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens

“…A compelling case demonstrates that as well as binding allergen-specific IgE, some allergens possess bioactivities which are essential to the development and maintenance of sensitisation to a wide range of unrelated allergens [ 1 , 2 ]. These bioactivities define the function of the allergenic protein in its host source, but upon interaction with structural elements of human mucosal surfaces they can cause disease, especially in individuals possessing an underlying genetic predisposition.…”

“…Group 1 allergens from HDM have been most extensively investigated as initiator allergens [ 2 , 11 , 12 ]. In HDM, they function as digestive enzymes and are excreted in faecal pellets which are inhalable by humans.…”

“…Similar permeability events have been reported for the nasal epithelium and skin [ 16 , 17 ] and linkage to allergy is suggested by claudin-1 expression being inversely proportional to the Th2 polarisation of immune responses [ 18 , 19 ]. The recent discovery that Group 1 HDM allergens have prothrombinase activity provides new insight into how this polarisation to allergic responses occurs and suggests a novel mechanism which might contribute to epithelial–mesenchymal cell transition and airway remodelling driven primarily by the innate effects of certain allergens [ 2 , 12 , 20 , 21 ]. The combination of allergen delivery, polarisation of adaptive responses and immunodominance by Group 1 HDM allergens is consistent with them being initiators of allergic responses to themselves and to unrelated allergens through a process of collateral priming of immune responses [ 2 , 11 , 12 , 14 ].…”

“…The identification and characterisation of initiator allergens creates opportunities for the design of small molecule interventions designed to target the agents whose activities promote and sustain allergic disease [ 2 , 11 , 12 , 22 ]. A prominent appeal of such an approach is that the targeting of a non-human, root cause trigger of disease should combine an attractive safety profile with a significantly wider range of efficacy benefits than can be achieved by targeting discrete downstream effector pathways (e.g., leukotriene antagonists, cytokine-specific biologics), or by the less selective action of corticosteroids [ 12 , 22 ].…”

“…A prominent appeal of such an approach is that the targeting of a non-human, root cause trigger of disease should combine an attractive safety profile with a significantly wider range of efficacy benefits than can be achieved by targeting discrete downstream effector pathways (e.g., leukotriene antagonists, cytokine-specific biologics), or by the less selective action of corticosteroids [ 12 , 22 ]. Attempting this type of intervention is now feasible following biological advances in understanding the molecular basis of allergenicity, and chemical advances in structure-based protease inhibitor design [ 2 , 11 , 12 , 22 ]. Thus, for the first time since the invention of allergen immunotherapy by Noon and Freeman in 1911, is it possible to envisage small-molecule pharmacotherapy aimed directly at the causative, non-human, aspect of allergy [ 23 ].…”