Macrocyclic protease inhibitors with reduced peptide character

摘要

A β-strand provides the basis of many peptide-protein interactions, such as the binding of a peptide substrate to a protease. Consequently, an important approach to the design of protease inhibitors involves stabilising the p-strand conformation in a peptidomimetic, thereby reducing entropy loss associated with ligand-receptor binding. Suitably constructed peptide macrocycles can do this effectively, but these structures are not ideal in that they retain considerable peptide-like character and are therefore susceptible to metabolic degradation. Researchers at the Universities of Adelaide, Bonn and Cologne have developed a new class of macrocyclic protease inhibitor in which a backbone amino acid is replaced with a planar pyrrole (Chua K.C.H., Pietsch M., Zhang X., Hautmann S., Chan H.Y., Bruning J.B., Gutschow M., Abell A.D. Angew. Chem. Int. Ed. 2014, 53, 7828-31).