Novel fluorinated pseudopeptides as proteasome inhibitors.

We have designed novel small inhibitors of rabbit 20S proteasome using a trifluoromethyl-beta-hydrazino acid scaffold. Structural variations influenced their inhibition of the three types of active sites. Proteasome inhibition at the micromolar level was selective, calpain I and cathepsin B were not inhibited.

α- and ß-hydrazino acid-based pseudopeptides inhibit the chymotrypsin-like activity of the eukaryotic 20S proteasome.

We describe the synthesis of a library of new pseudopeptides and their inhibitory activity of the rabbit 20S proteasome chymotrypsin-like (ChT-L) activity. We replaced a natural α-amino acid by an α- or a ß-hydrazino acid and obtained inhibitors of proteasome up to a submicromolar range (0.7 µM for molecule 24b). Structural variations influenced the inhibition of the ChT-L activity. Models of inhibitor/20S proteasome complexes corroborated the inhibition efficacies obtained by kinetic studies.