Rheumatoid arthritis, type I diabetes, coeliac disease and multiple sclerosis are common (auto) immune diseases that all have a well established HLA-association. This is likely the result of inappropriate T cell responses to peptides derived from (auto) antigens bound to the disease predisposing HLA-molecules. These diseases affect an estimated 6 million individuals in Europe alone and there are no established cures. Many of the key players involved in antigen presentation have now been identified.
Simultaneously, combinatorial library approaches and novel developments in organic chemistry and molecular modelling now allow the rational synthesis of large numbers of related compounds that can be screened for biological activity in high throughput test-systems. The purpose of the current proposal is to bring together laboratories that have developed platform technologies with laboratories that study antigen presentation to develop effective inhibitors of antigen presentation. These include MHC/HLA-blocking compound s, T cell receptor blocking compounds, and enzyme inhibitors. We aim to achieve the design of inhibitors with computer-aided modelling.
Next a dedicated synthesis protocol will be used to simultaneously synthesize the lead compounds and variants thereof. In the second approach dedicated (peptide) libraries will be designed and synthesized that are based on limited structural information concerning the target antigen or a potential lead compound. In both approaches the efficacy of the compounds synthesized will be tested in functional assays followed by optimisation of the most promising lead compounds.
The project is highly dependent on the intensive collaboration between the laboratories that have the platform technologies operational and the other participants that have identified potential target antigens and test systems. The development as well as marketing of these drugs is aided by the close collaboration with an SME word king in the field of the proposal.
Call for proposal
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