Abstract

Diverse evidence from epidemiological surveys and investigations into the molecular basis of allergenicity have revealed that a small cadre of 'initiator' allergens are responsible for promoting the development of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. Pre-eminent among initiator allergens are those derived from house dust mites (HDM). In these mites, group 1 allergens function as cysteine peptidase digestive enzymes to which humans are exposed by inhalation of HDM fecal pellets. This protease nature confers these allergens with 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 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 rationale for, and structure-based drug design of, the first-in-class representatives of allergen delivery inhibitors which are aimed at neutralizing the proteolytic effects of HDM group 1 allergens which are essential to the development and maintenance of allergic diseases.