Targeting A Complement Receptor That Regulates Inflammatory Disease (2007–2009)
There are over 100 inflammatory diseases, such as arthritis, inflammatory bowel diseases, sepsis, shock, heart disease, ischemia-reperfusion injury, atherosclerosis, multiple sclerosis, etc. Current antiinflammatory drugs are either not very effective or are compromised by high costs, safety concerns, or reduced effectiveness over time. Complement proteins are natural substances in human blood that protect against infection and injury by causing inflammation which is a desirable component of the immune response. One of these complement factors known as C5a is now thought to be a pivotal component of the complement system of human blood proteins that are synthesized during immune defence against infection. However when C5a is overexpressed or left unregulated it can lead to inflammatory diseases and is now throught to be a key factor in disease progression. In other work, we have been investigating the blockade of various human complement proteins (C5a, C3a, MAC), resulting in a number of new small molecules that can selectively affect, and allow us to probe their specific importance in, the human immune response. This project seeks to develop new compounds (suitable for development into drugs) that can block the binding of C5a to its receptor on the surface of immune cells, thereby preventing the pro-inflammatory actions of C5a. Such compounds have the potential to be new classes of antiinflammatory drugs that treat disease progression rather than just the symptoms of disease. We have previously created the first small molecule antagonists that helped to establish the importance of human C5a in inflammatory disease. We now need to find out how small molecules bind to the receptor for C5a, in order to more effectively block its action in vivo and develop improved antiinflammatory drugs for man.