FOLDAPPI · Foldamers against protein-protein interactions

The Foldappi proposal aims to investigate the potential of aromatic amide Foldamers to disrupt protein-protein interactions. The scientific goals of the project include: 1. development of synthetic methods to build foldamers with different R-group chemistries 2. development of strategies to target foldamers to protein surfaces 3. measuring in vitro properties of foldamer(s) to assess ADME profiles of these molecules In this proposal we propose to explore the use of quinoline-derived aromatic amide foldamers developed at the University of Bordeaux to inhibit protein-protein interactions, namely the interaction between interleukin 4 (IL-4) and its receptor. These foldamers have a very well defined structure that lends itself to the rational design of substituents and the production of focused combinatorial libraries of foldamers capable of interacting with the IL4/IL-4R binding epitope. They are also large enough to block a protein-protein interaction, a feat that is not possible with small molecules. The cytokine IL-4 is a key regulator of the immune system determining the formation of immune cells and immunoglobulin class switching. IL-4 is critically involved in misguided immune reactions during atopic diseases as allergy and asthma. In spite of its importance as a drug target, no small molecule inhibitor of the Il-4/IL-4R has been reported so far, warranting the use of foldamers to do the same. The three partners involved in this cooperation, namely UCB Pharma, Université Bordeaux I and Universität Würzburg each have unique expertises necessary to bring this project to completion. This combination will produce breakthrough knowledge and insights into developing chemistries that can impact in health and medical fields. Moreover, this project will contribute to the personal development of the scientists involved by improving their interdisciplinary knowledge, as well as their communication and experimental skills.