Development of small molecule inhibitors of FcεRI
Prof D Cox
Dr M Adamo
Monday, December 02, 2019
Competition Funded PhD Project (Students Worldwide)
Allergic diseases are one of the most common diseases in the Western world. A report from the American academy of allergy, asthma and immunology indicated that between 40-50% of children are sensitized to at least one allergen. Its most severe presentation is anaphylaxis with an incidence of approximately 20 per 100,000 person-years.
Allergies occur when patients form IgE antibodies to a foreign protein. When subsequently exposed to the protein the IgE-antibody complex binds to the Fc receptor on basophils and mast cells. Binding to FcεRI triggers degranulation of the target cell which specifically releases histamine and other inflammatory cytokines. These agents cause bronchoconstriction and vasodilation leading to difficulties breathing and lifethreatening hypotension.
Current treatment of allergic reactions is mainly symptomatic including anti-histamines, steroids, adrenaline and bronchodilators. However, none of these alter the underlying disease, thus, there is a need for more effective agents to treat allergic reactions. One possibility is to target the IgE-FcεRI interaction. This could be achieved by blocking FcεRI with a small molecule. We will use the expertise that we have developed in discovering small molecule inhibitors of FcγRIIa-IgG to develop small molecule inhibitors of the IgE-FcεRI interaction.
There are a number of potential benefits to an orally active small molecule inhibitor of Fcε. Firstly, it will be a lot cheaper than a monoclonal antibody. Secondly, it can be used prophylactically where patients could take a daily tablet during hay fever season to prevent symptoms. Finally, it could also be used in an emergency situation where a tablet could be taken when symptoms develop to prevent further deterioration in the patient.