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.

Automated summary

Rhomboid proteases are important enzymes involved in various biological processes and human diseases. Recent research has shown that solid-phase synthesis of peptidyl alpha-ketoamides allows rapid synthesis and optimization of rhomboid protease inhibitors, with the primed site binding part being crucial for potency.