Medicinal chemists at Domainex collaborated with scientists at St George's University of London and the University of Manchester, to develop novel chemical compounds known as Allergen Delivery Inhibitors (ADIs); which have the potential to become a new paradigm in the treatment of asthma. Blocking the bioactivity of allergens was considered an attractive approach as a small-molecule therapy for allergic diseases, but had not been attempted previously.
This project focussed on inhibiting a protease excreted by house dust mites (a group 1 allergen), which are believed to be one of the commonest causes of domestic allergy, and a major trigger for asthma attacks
Group 1 allergens of house dust mites (HDM) 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 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.
This programme successfully led to the nomination of a candidate drug (CD) and funding is now being sought to progress into clinical trials. In addition to the nomination of a CD the programme has identified several developable back up compounds from chemically distinct and mechanistically distinct series allowing a robust patent portfolio to be generated.
The project was funded by the Wellcome Trust SDDI.
Newton G et al. (Nov 2014) 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. J. Med. Chem.