1 research outputs found
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
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