Characterisation of Novel FCγRIIa Inhibitors

MCT Research Talks – 10th, April 2017

Research talks were presented by Sheila Zarros, Tatyana Devine, Afnan Ali and Padraig Norton. Tatyana and Sheila were talking about challenges in the characterisation of novel FCγRIIa inhibitors.

Fc receptors are a widely distributed family of receptors that mediate cellular responses to antibodies or immunoglobulins (Ig). The Fc gamma receptor II, FcgRII (also known as CD32) is a low-affinity receptor for Fc portion of immunoglobulin G (IgG) and has two isoforms FcgRIIa and b. Fcg RIIa is widely expressed by human innate immune cells and is the only Fc gamma receptor found on human platelets.

Our group and others have demonstrated the significance of this receptor in the activation of platelets by bacteria, suggesting that it could be an important target in the treatment of sepsis. Its implications in rheumatoid arthritis, cancer pathogenesis, allergic reactions and flu virus-induced thrombocytopenia were also demonstrated.

Our project is focused on characterisation of novel small molecule compounds designed for targeting FcgRIIa receptor’s IgG binding site to inhibit bacteria-induced platelet aggregation in primary human plasma and investigation of their interactions with the FcgRIIa using surface plasmon resonance technology.

Afnan Ali reported on the role of the Fc gamma Receptor IIa (FcγRIIa) in platelet activation. Platelets express the FcγRIIa and this receptor has been identified as a key receptor in bacterial activation of platelets leading to thrombocytopenia and platelet activation. The aim of this study was to identify drugs that could be re-purposed for the treatment of sepsis and immune-mediated thrombocytopenia. We identified 42 drugs predicted to inhibit binding of IgG1 to the FcγRIIa using virtual high throughput screening. This included 20 antibacterial agents, 3 anti-fungals, 3 antiviral agents, 7 antineoplastics and 3 immunosuppressives. A selection of drugs were tested for inhibition of platelet adhesion to IgG, S. aureus-induced platelet aggregation and assessed for platelet activation. This work has identified multiple drugs that have potential to be to be repositioned for thrombocytopenia, sepsis and autoimmune disorders, as well as providing a possible mechanism of action to explain the immunosuppressive effects of some anti-neoplastics and immunosuppressive drugs.