S1669 Gl1001 Attenuation of Acute Colitis in a Mouse DSS Model Is Associated with Inhibition of Its Target, ACE2

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

“…These have been used previously to explore the therapeutic utility of ACE2 inhibition in animal models of human irritable bowel disease (IBD). MLN-4760, at high doses (300 mg/kg, b.i.d) in mice, was disease-modifying in the dextran sodium sulfate (DSS) model , which points to a potential therapeutic utility for ACE2 inhibitors. However, the high doses used in the study are indicative of suboptimal drug-like properties, and so here we set out to identify improved Bicycle -based ACE2 inhibitors.…”

“…The TATA scaffold acquired a twisted boat conformation as opposed to the previously strained chair conformation observed in the BCY15291 structure. While this may come at a minor energy penalty in isolation, we hypothesized that 4MePhe 4 substitution drives the TATA conformational change, forcing the Bicycle C-terminal Ala Ti to adopt a new conformation, which then forces His 12 to a new position. In BCY15291, His 12 engages in hydrophobic interactions with ACE2 Tyr 50 .…”

“…While this may come at a minor energy penalty in isolation, we hypothesized that 4MePhe 4 substitution drives the TATA conformational change, forcing the Bicycle C-terminal Ala Ti to adopt a new conformation, which then forces His 12 to a new position. In BCY15291, His 12 engages in hydrophobic interactions with ACE2 Tyr 50 . In the newly adopted conformation in BCY20862, Bicycle His 12 engages in hydrophobic interactions with Bicycle Leu 8 and Bicycle Pro 9 as well as ACE2 Val 343 .…”