Use of affimer technology to discriminate between agonist- and antagonist-induced conformational changes in the Cyclic-Nucleotide Binding Domain (CNBD) Protein, EPAC1

There is an urgent need to develop new therapeutic strategies to combat the “chronic inflammation” associated with cardiovascular diseases (CVDs), which are the cause of some 187,000 premature deaths in the UK per year. Chronic inflammation can develop due to increased levels of inflammatory “messengers”, or cytokines, in the circulation. In the case of conditions like atherosclerosis, this inflammation involves excessive “leakiness” and increased attachment of white blood cells to the vascular endothelial cells (VECs) that line the blood vessels. This causes long term damage, including blocked arteries and blood clots, which can lead to heart attacks or strokes. Moreover, attempts to use “stents” to restore blocked arteries often fail due to localised inflammatory activity. We have discovered that activation of the enzyme, EPAC1, can suppress this inflammatory activity. We will therefore generate “artificial antibodies”, or “Affimers”, which will allow us to develop new activators of EPAC1 with the potential to suppress damaging inflammation in VECs.