Title : Synthesis of proline-derived modules and their application in the development of protein secondary structure mimetics
We developed a toolkit of Proline-derived Modules (ProMs), which can be used to prepare peptide-based inhibitors of protein-protein interactions. These modules consist of rigidified diproline units and can induce conformational preorganization in peptide ligands, thereby imitating naturally occurring protein secondary structures. ProM-1 and ProM-2 were successfully used in the construction of PPII-helical peptides as inhibitors of the EVH1 domain, which plays an important role in cell migration during breast cancer metathesis. In constructs, ProM-5 was used as an N-cap for short peptides to induce α-helices.
While this α-helix inducing effect of ProM-5 was proven for idealized short peptides, we are currently working to apply the concept to more complex biological systems such as short α-helical peptides derived from the α1-helix found in ACE2, which SARS-CoV-2 and other coronaviruses employ for cell entry. Such peptides may then serve as inhibitor ligands for this specific interaction. Further, new ProM units are being synthesized by structural variation of known modules to improve binding to the EVH1 domain or to address other PPII-helix derived domains.