Dermot Cox

Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, IRELAND

Abstract:

FcγR is a family of receptors that specifically bind IgG and its most important member FcγRIIa plays a key role in phagocytosis. In autoimmune diseases excessive formation of immune complexes binds FcγRIIa and plays an important role in pathogenesis. In animal models of rheumatoid arthritis activation of monocyte FcγRIIa leads to over production of TNFα, which drives the inflammation of the joints. There is also evidence of a role for FcγRIIa in infection where thrombocytopenia is a typical symptom of septicemia and viral haemorrhagic fevers. This thrombocytopenia is due to excessive platelet activation, a key factor in disseminated intravascular coagulation. Platelet activation by Staphylococcus aureus is mediated by bacteria-bound antibody binding to FcγRIIa on the platelet surface. FcγRIIa has also been shown to be important in Dengue haemorrhagic fever where it facilitates viral uptake by monocytes. Using the crystal structure of FcγRIIa we developed a pharmacophore for IgG binding. This was used for virtual high-throughput screening of the ZINC database. The hits were screened in vitro to confirm their activity and a chemical template identified. Derivatives were synthesized and screened for biological activity. Currently derivatives have been synthesized with IC50 values of 1 μM in a range of assays including platelet adhesion to IgG, heat-agglutinated IgG-induced platelet aggregation and S. aureus-induced platelet aggregation. These compounds have the potential to be effective treatments for rheumatoid arthritis, sepsis and Dengue fever.