Development of innovative anti-inflammatory drugs

We introduced a novel concept of the functional role of CRP as a ‘pro-inflammatory agent'. This concept is based on our findings that pentameric (p)CRP can undergo a conformational change to monomeric (m)CRP, which is highly pro-inflammatory and pro-coagulant, and induces a localised inflammatory reaction that aggravates many diseases. We have shown that pCRP to mCRP dissociation occurs on the surface of ‘stressed cells', such as activated necrotic or apoptotic cells, and on microparticles (MPs) circulating in blood. For example, the surface of activated platelets causes a rapid dissociation of pCR to mCRP. We have also described mCRP formation induced by misfolded proteins, such as Alzheimer's plaques, as a clearance mechanism that can ‘overshoot' in pathological situations. We are now developing inhibitors of CRP dissociation that can form the basis of a novel therapeutic approach for a range of inflammatory diseases including atherosclerotic plaque instability and autoimmune diseases. Technologies/models to learn/apply: Drug design and development, medicinal chemistry, biotechnology, various animal models of inflammation, myocardial infarction, atherosclerosis, stroke, Alzheimer's disease.