Rapid Synthesis of Internal Peptidyl Α-Ketoamides by on Resin Oxidation for the Construction of Rhomboid Protease Inhibitors

Rhomboid proteases are intramembrane serine proteases, which are involved in a wide variety of biological processes and have been implied in various human diseases. Recently, peptidyl alpha-ketoamides have been reported as rhomboid inhibitors with high potency and selectivity - owing to their interaction with both the primed and non-primed site of the target protease. However, their synthesis has been performed by solution phase chemistry. Here, we report a solid phase strategy towards ketoamides as rhomboid protease inhibitors, allowing rapid synthesis and optimization. We found that the primed site binding part of inhibitors is crucial for potency.