Michael Thai Trung King Molecular and celluar therapeutics
Royal College of Surgeons in Ireland
Abstract:
Aims of study: FcγRIIA-mediated platelet activation is known to play a role in a number of diseases including infective endocarditis, sepsis and drug induced thrombocytopenia but there are no inhibitors to this receptor. Based on the binding interaction of IgG with FcγRIIA, a pharmocophore was derived to be used as a template for the generation of small molecules to be tested for inhibition of the Fc\γRIIA receptor.
Basic study design: The development of compounds is based on molecular modeling computations of the FcγRIIA -IgG binding interaction and the initial screening of lead compounds.
Methods: First generation compound synthesis is based upon the pharmacopore derived from the lead compounds and incorporating novel facile building blocks using cost effective materials. Primary biological screening via platelet adhesion assay followed by secondary screening involving bacterial-induced platelet aggregation.
Results: A novel synthetic route to obtain a series of novel compounds which possess a versatile synthetic route that can be easily derivitised. Among the compounds synthesized, initial screening showed promising if not equal to the preliminary compounds giving IC50 between 6µM to 40µM.
A particular compound of interest gave an IC50 of 34µM ,N=3, P<0.0001 and have shown to be specific in that they do not inhibit platelet adhesion to TRAP activated fibrinogen, or platelet aggregation stimulated by ADP. The compound also showed activity against Staphylococcus aureus-induced platelet aggregation
Conclusions: We successful developed a novel synthetic route to build a series of small compounds that shows activity against bacterial induced platelet aggregation, heat-agglutinated IgG-induced aggregation, and platelet adhesion to IgG. These compounds could be used for the treatment of sepsis, and immune-mediated thrombocytopenia in order to inhibit bacterial/IgG-induced platelet activation without compromising normal platelet function.
Keywords: FcγRIIA , anti-infectives, cardiovascular drug discovery
