Expansion of the amide substituent in ketoamide inhibitors of rhomboid proteases increases their potency and cellular availability

Abstrakt

Rhomboids are serine intramembrane proteases which have manifold biological functions in all domains of life and are associated with various diseases such as malaria, Parkinson's disease, and different types of cancer. To date, peptidyl α-ketoamides modified by a hydrophobic substituent ('tail') at the ketoamide nitrogen are the most potent and selective inhibitors of rhomboid proteases available, useable for chemical intervention with rhomboid function.

Here, we use the Escherichia coli rhomboid protease GlpG as model to explore the extension of the hydrophobic substituent as possibility to increase the inhibitory potential and cellular uptake of ketoamides which might allow a minimization of the peptidyl part.