Macrocyclic Protease Inhibitors with Reduced Peptide Character

There is a real need for simple structures that define a β-strand conformation, a secondary structure that is central to peptide-protein interactions. For example, protease substrates and inhibitors almost universally adopt this geometry on active site binding. A planar pyrrole is used to replace two amino acids of a peptide backbone to generate a simple macrocycle that retains the required geometry for active site binding. The resulting β-strand templates have reduced peptide character and provide potent protease inhibitors with the attachment of an appropriate amino aldehyde to the C-terminus. Picomolar inhibitors of cathepsin L and S are reported and the mode of binding of one example to the model protease chymotrypsin is defined by X-ray crystallography. The incorporation of a pyrrole into a peptide backbone generates simple macrocycles that adopt a β-strand geometry. The attachment of a P1 amino aldehyde to these templates then gives rise to potent protease inhibitors (see example, top, which has Ki values of 440 pM and 920 pM against the cysteine cathepsins L and S, respectively). A crystal structure of a related derivative bound to chymotrypsin (see picture, bottom) confirms the design. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.