JOINT EPSRC/MRC CHEMICAL BIOLOGY Pharmacological targeting of cytosolic calpain-1: The development of novel inhibitors

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White blood cells, such as neutrophils and lymphocytes combat infection by leaving the blood circulation to enter the tissues and destroy infecting microbes. However, there are a number of inflammatory disease in which these cells are the cause of the problem. In rheumatoid arthritis, for example, white cells continually leave the blood stream and migrate to the affected joints, where they are inappropriately activated to ?attack? the tissues of the joint. This causes a progressive destruction of the joint. Unsurprisingly, considerable effort has been made in trying to understand the mechanism by which white cells leave the blood stream so that effective treatments can be devised to stop this. One of the successes has been the use of monoclonal antibodies to block the molecular signals which ?call? white cells to leave the blood stream. However there are problems, with this approach. Firstly, the treatment involves a costly infusion of antibody which must be done in hospital. Secondly, antibodies are highly selectively and can only recognise, and so block, one set of molecules. Since there may be a range of molecules ?calling? to the white cells, any single monoclonal antibody may fail to be effective. We have therefore looked at the mechanics of how the white cells leave the blood stream, because this must be a common event regardless of precisely which calling molecules are involved. We have found that the cells change shape in order to slip through the blood vessel walls. This involves an apparent large increase in the surface area of the cells. We have evidence that this occurs because the membrane of the cells is initially very wrinkled. These wrinkles unfurl when the protein links which hold them together are broken by an enzyme called calpain-1. If this enzyme is inhibited, the unfurling stops and the speed which white cells can leave the blood is greatly reduced. This would be the basis for an anti-inflammatory drug which could be simply taken by mouth. Luckily, we already know of some synthetic molecules which inhibit the enzyme. Furthermore, we know where they bind to the enzyme. In this project, we plan to use this knowledge to ?tailor? this family of molecules to become more potent and selective only for calpain-1. This will minimise the possibility of unwanted side effects by inhibition of other enzymes which also cut proteins.