Chimeric helices with improved properties for inhibiting target protein-protein interactions – CHIMPP2I

Protein-Protein interactions (PPIs) are critically involved in numerous biological events. They are also associated with a number of pathological situations, and thus represent important therapeutic targets. Inhibiting PPIs is challenging in part because of the difficulty to target the extended surfaces at such interfaces (1000–2000 Å2). Alpha-helices are prevalent among protein secondary structural motifs and often play the key role of recognition elements between proteins. Hence, isolated peptide segments corresponding to exposed bioactive helical surfaces (500–2,000 Da) may represent ideal candidates for the development of novel pharmacological tools and drugs. However, this appeal has met with limited success because isolated peptides typically adopt random structures, are susceptible to degradation by circulating enzymes, and with few exceptions generally display poor capacity, if any, to enter cells, thus limiting their use to extracellular targets. Thus, chemical approaches aimed at reinforcing or mimicking protein secondary structure elements are of current interest to inhibit PPIs, develop innovative medium-size therapeutics complementary to small molecules and biologics. As shown by the unprecedented number of marketing approvals in 2012 and the number of peptide therapeutics in clinical trials, there is a continually expanding contribution of peptides to the worldwide pharmaceutical market. Though several methods based on side chain modifications exist to increase alpha-helicity, there is a need to explore new approaches that can ultimately be combined to generate peptidomimetics with tailored properties. Those based on foldamer (i.e. synthetic folded oligomers) chemistry show promises for mimicking alpha-helices. However, technologies based on foldamers to improve the recognition properties of prototype polypeptides while diminishing the susceptibility to degradation by proteases have thus far remained limited and very few foldamer/protein complexes have been described at atomic resolution.
This project will move a step forward towards this goal, by (1) developing chimeric foldamer helices with improved properties for mimicking natural alpha-helices and inhibiting target PPIs; and (2) exploring and exploiting the molecular basis of protein surface recognition by such foldamers. This project will bring together two academic laboratories (CBMN, Pessac – Partner 1 & IGBMC, Illkirch – Partner 2) with prominent expertise in peptidomimetic and foldamer chemistry, chemical biology and structural biology of target PPIs and one SME (UREkA, a subsidiary from ImmuPharma plc – Partner 3) with a strong focus on the development of peptide-based drugs and new technologies for mimicking alpha-helices and interested to strengthen its patent portfolio. A multi-disciplinary and multi-group effort is needed to realize the full potential of this emerging technology from fundamental principles to pharmaceutical requirements. The aforementioned technology (that is proposed to be named UrelixTM) will be a milestone in the design of foldamer-based PPI inhibitors of pharmaceutical interest.