Design and Synthesis of New Oligopeptidic Parvulin Inhibitors

: Pin1 catalyzes the cis-trans isomerization of pThr-Pro or pSer-Pro amide bonds of different proteins involved in several physio/pathological processes. In this framework, recent research activity is directed towards the identification of new selective Pin1 inhibitors. Here, we developed a set ( 5a - p ) of peptide-based Pin1 inhibitors. Direct-binding experiments allowed the identification of the peptide-based inhibitor 5k as a potent ligand of Pin1. Notably, 5k binds Pin1 with a higher affinity compared to Pin4. The comparative analysis of molecular models of Pin1 and Pin4 with the selected compound, gave a rational explanation of the biochemical activity, and pinpointed the chemical elements that, if opportunely modified, may further improve inhibitory potency, pharmacological properties and selectivity of future peptide-based Parvulin inhibitors. Since 5k showed a limited cell penetration and no antiproliferative activity, it was conjugated to a polyarginine stretch, known to promote cell penetration of peptides, to obtain R8-5k derivative, which displayed an anti-proliferative effect on cancer cell lines compared to non-tumor cells. The effect of R8 on cell proliferation was also investigated. This work doubts the application of the R8 strategy for the development of cell penetrating antiproliferative peptides since it is not inert.