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

Cytoskeleton remodeling 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 will target actin filament turnover, which regulates cell shape, motility, migration, division, and intracellular transport. So far, drug candidates targeting actin cytoskeleton remodeling act upstream of the signaling pathways on small RhoGTPases or on their direct downstream regulated kinases, very few of them reached the market. This project is focused on cofilin, a main actin-depolymerizing factor, which stands downstream of the actin signaling pathway. LIM kinases (LIMKs) are major regulators of cofilin: they phosphorylate it leading to its inactivation. Since 2008, many small-molecules inhibitors of LIMK kinase activity have been developed to prevent their action on cofilin. However, only one has reached clinical trial, with no published results. In this project, we devised a new paradigm to develop highly selective and specific inhibitors of cofilin phosphorylation based on the disruption of LIMKs/cofilin protein/protein interaction. This approach is motivated by the atypical interaction between LIMKs and cofilin, recently resolved by X-Ray crystallography. This interaction is not dependent on the recognition of the amino acids surrounding the phosphorylatable Ser3 of cofilin but is exclusively due to the binding of a distant a-helix of cofilin within a groove of LIMKs. The goal of this project is to disrupt this interaction by using a promising class of therapeutic molecules, “stapled peptides”: short cyclic peptides that adopt an a-helical conformation, exhibiting cell penetrating abilities and favorable pharmacokinetics.

The Center for Molecular Biophysics (CBM) develops research at the interface of chemistry, biology and physics to study the molecular mechanisms that sustain life or dysfunctions leading to diseases. CBM scientists are investigating the structure, dynamics and interactions of biomacromolecules at the molecular, cellular and whole-organism scales. Biomedical imaging is also a strong research theme at CBM. CBM hosts a wide range of scientific instruments, especially the platform MO2VING that offers technical and scientific support for both molecular characterization of biomolecules and biological imaging from cells to small animals. With its 5 sub-platforms: NMR, MS, P@CYFIC (confocal imaging and flow cytometry analysis), MRI and TAAM-In vivo Imaging, MO2VING brings together multiple areas of expertise and offers a comprehensive service offering ranging from small molecules to small animals.

Key words: biochemistry, chemistry, biology, biophysics, imaging, structural biology, molecular and cellular biology, therapeutic targets, cell signaling

Master 2 degree in biology
Working experience in research
Strong skills in molecular biology, biochemistry, cell biology, and imaging

Interest to discover and understand new molecular mechansims involved in physological and pathological processes

Other human skills will be appreciated : autonomy, personal investment, scientific curiosity, and team spirit.

As the thesis subject is part of a project gathering 5 multidisciplinary teams, an open-mind and capacities to interact with different people are also required