Guy Gouarin's PhD defense

Pin1 is a rotamase, an enzyme known to catalyse the peptidyl-prolyl bond isomerisation. At the crossroads of multiple biochemical pathways, its deregulation is associated with numerous pathologies. The development of some cancer has been linked to its overexpression. As such, multiple research groups have been interested in the development of a great variety of inhibitors going from small synthetic or natural molecules to peptides. However, finding the good balance of properties like selectivity, affinity, metabolic stability or biological membrane permeation has proven to be challenging. That is why very few molecules reach the clinical trial step. Furthermore, neither the catalytic mechanism nor the allosteric regulation of the enzyme is fully understood yet. A better understanding of those processes should allow more efficient development of new inhibitors. Moreover, fluorine is considered as a key in medicinal chemistry and is slowly becoming a must in the pharmaceutical industry. The use of fluorine has demonstrated a great interest in medicinal chemistry. The incorporation of fluorine atoms is known to modulate the biophysical and chemical properties of biomolecules, thus conferring highly favorable pharmacokinetic and pharmacodynamic profiles.

The aims of this thesis were to develop new peptidic and peptidomimetic Pin1 ligands. Based on our expertise in the synthesis of fluorinated amino acids and their incorporation into peptides, we rationally designed two fluorinated peptide series. The first one incorporates a fluorinated proline analogue able to introduce conformational constraint on the peptidyl-prolyl bond while the second series bears a fluorinated bioisostere of phosphate to enhance the metabolic stability of the ligands. A set of peptides in both series have been successfully synthesized, and their affinity for Pin1 has been assessed by NMR experiments. From those results, a structure-activity relationship study has been performed highlighting some key features to promote good and selective binding affinity for Pin1 domains.