| Project Detail |
Roughly 1% of the world’s population is affected by rheumatoid arthritis (RA); a devastating autoimmune disease causing cartilage destruction and bone erosion. Recent evidences suggest that dysregulation of Peptidyl Arginine Deiminase (PAD) levels are associated with the onset of the disease, leading to the production of antibodies targeting the citrullinated neoepitopes. The exact role of each of the PAD isotypes in these pathological processes is unknown and fundamental questions on the intracellular activation mechanism and substrate specificity remain unanswered. Moreover, isoform specific and high affinity enzyme inhibitors are lacking thereby not only hampering fundamental research towards each PAD isotype, but also excluding PAD as a potential therapeutic target for these diseases.
This proposal is aimed at developing innovative chemical biology- and molecular tools to study PAD functioning and protein citrullination in health and disease. The work reflects my interdisciplinary experiences as well as my interest I have obtained over the last years in chemical immunology as well as my ambition to improve patients wellbeing. More detailed, I aim to 1) find unknown PAD modulators, 2) find PAD substrates, 3) find selective and high affinity PAD inhibitors using enzyme-templated inhibitor evolution as novel lead discovery strategy, 4) explore multifunctional targeted PAD ‘nanosponges’ as advanced avidity-based nanomedicine approach and 5) explore unprecedented citrulline ‘eraser’ enzymes by innovative chemical biology strategies.
The workpackages described in this ambitious and highly interdisciplinary proposal deliver high-end molecules and methods that can be used to answer fundamental (conflicting) questions on citrullination and PAD biology. Moreover, possible molecular leads and advanced therapeutic insights are provided thereby centring PAD as therapeutic target for citrulline-mediated autoimmune diseases such as RA. |
