Structure-Guided Chemical Optimization of Bicyclic Peptide (Bicycle) Inhibitors of Angiotensin-Converting Enzyme 2

Angiotensin-converting enzyme 2 (ACE2) is a metalloproteasethatcleaves angiotensin II, a peptide substrate involved in the regulationof hypertension. Here, we identified a series of constrained bicyclicpeptides, Bicycle, inhibitors of human ACE2 by panninghighly diverse bacteriophage display libraries. These were used togenerate X-ray crystal structures which were used to inform the designof additional Bicycles with increased affinity andinhibition of ACE2 enzymatic activity. This novel structural classof ACE2 inhibitors is among the most potent ACE2 inhibitors yet described in vitro, representing a valuable tool to furtherprobe ACE2 function and for potential therapeutic utility.