The research performed over the last four years has given rise to a sea-change in our understanding of the organisation of glycoprotein receptors and their mechanism of activation and has identified candidate lead agents for therapeutic exploitation. The work has given rise to fundamental changes in our understanding of the organisation of glycoprotein receptors in the membrane, including the observation many exist as a mixture of monomers and dimers and do not adopt a unique conformation on dimerisation. The work has also uncovered several mechanisms of receptor dimerisation and shown how these work in synergy to drive clustering and intracellular signalling. We have shown how advanced methodology including microscopy, proteomics and lipidomics and flow-based models can progress our understanding of platelet glycoprotein receptors, as well as generating novel agents (small molecule inhibitors, biologics, fluorescent probes, mouse models) to further study their function.
TAPAS has also developed a cohort of 15 highly skilled and specialist researchers that will lead to further academic-industry interactions and collaborations. Several of the several of the ESRs have already secured prestigious postdoctoral positions in leading laboratories and in industry, while the others are at advanced stage of completion of their doctoral thesis.
A key benefit of the TAPAS programme is the synergy in expertise between academic laboratories and the private sector in terms of understanding and commercial exploitation of processes surrounding thrombosis and haemostasis, molecular target validation and assay development. By working together in this network, the ESRs have gained a unique insight into ‘team’ science, including handling of large data sets, in vivo analyses, patient studies and commercialisation.
TAPAS has fostered accelerated advancements in the development of antiplatelet agents targeted at platelet glycoprotein receptors for prevention of thrombosis with reduced morbidity relative to current antiplatelet drugs and so will be of significance beyond the lifetime of TAPAS. Nevertheless, the societal benefits are many years away as the primary focus has been on generating knowledge that provides a base for translation. TAPAS has helped to create interest in Biotech/Pharma in regard to targeting platelet glycoprotein receptors in thrombosis. Further, this has taken place in parallel with early phase clinical trials on a GPVI-blocking Fab, glenzocimab in ischaemic stroke from the Biotech Acticor. The precursor of glenzocimab, 9012, has been shown to powerful inhibit platelet activation.
