Orthogonal dynamic assembly for peptidic engineering – OrthoPep

Cyclopeptides are an interesting class of therapeutics to target protein-protein interactions (PPIs) considering their non-toxicity, stability, and ability to mimic the large interacting domain of a protein. But, their rational molecular design is not straightforward, and their sequence optimization needs expensive, time-consuming and non-sustainable cycles of syntheses and testing towards the biological target. Alternatively, target-directed Dynamic Combinatorial Chemistry (tdDCC), involving reversible reactions under thermodynamic control, is a powerful tool to simultaneously synthesize large library of compounds, and identify potent inhibitors, upon addition of the targeted protein, by re-equilibration of the library and amplification of the best binders. But this methodology has been essentially applied to simple libraries of small compounds involving in general only one dynamic reaction. The OrthoPep project aims at enriching the molecular complexity of the method by applying it to peptides through multiple orthogonal dynamic reactions. This could allow to simultaneously screen different essential features of cyclopeptides as PPIs inhibitors starting from generic peptidic templates.