Towards a new therapeutic strategy targeting cytoskeleton dynamics by developping stapled Peptides to selectively inhibit LIMKs/Cofilin interaction – PeLiCo

Cytoskeleton remodelling is a dynamic process involved in most physiological and pathological events. Many drugs target microtubule turnover, but are often associated with side effects and resistance. In this project, we want to target actin filament turnover, which regulates cell shape, motility, migration, division. So far, most drugs targeting actin cytoskeleton remodelling act upstream of this signalling pathway, and very few have reached the market. Here, we will target cofilin, an actin-depolymerizing factor, which stands downstream of the pathway. LIM kinases (LIMKs) are the main regulators of cofilin: they phosphorylate it leading to its inactivation. LIMKs are misregulated in many pathologies. Many small molecules inhibiting the kinase activity of LIMKs have been developed to prevent their action on cofilin. However, only one has reached the clinical stage, with no published results. Actually, achieving selective inhibition of specific protein kinases is challenging, and off-target interactions frequently occur with unrelated kinases. Moreover, a small molecule that targets the active site of a given kinase does inhibit the phosphorylation of all its potential substrates. That is why, we want to inhibit cofilin phosphorylation by a completely different approach based on a new paradigm: disruption of the protein-protein interaction between LIMKs and cofilin, in order to develop highly selective and specific inhibitors. This approach is motivated by the very atypical LIMKs/cofilin interaction, exclusively due to the binding of an alpha-helix of cofilin with a groove of LIMKs. We will disrupt this interaction by using a promising class of therapeutic molecules, “stapled peptides”: short cyclic peptides adopting an alpha-helical conformation and exhibiting cell penetration abilities and favourable pharmacokinetic properties. Our project will bring valuable contribution to develop chemical biology tools with a direct drug discovery perspective.