7Q28

Crystal structure of Angiotensin-1 converting enzyme C-domain in complex with dual ACE/NEP inhibitor AD012

Summary for 7Q28

• Entry DOI: 10.2210/pdb7q28/pdb
• Descriptor: Angiotensin-converting enzyme, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: angiotensin-1 converting enzyme, dual inhibitor, nep, metalloprotease, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 70986.51

Authors

Cozier, G.E.,Acharya, K.R. (deposition date: 2021-10-23, release date: 2022-02-16, Last modification date: 2024-10-23)

Primary citation

Arendse, L.B.,Cozier, G.E.,Eyermann, C.J.,Basarab, G.S.,Schwager, S.L.,Chibale, K.,Acharya, K.R.,Sturrock, E.D.
Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition.
J.Med.Chem., 65:3371-3387, 2022

PubMed Abstract: Selective inhibition of the angiotensin-converting enzyme C-domain (cACE) and neprilysin (NEP), leaving the ACE N-domain (nACE) free to degrade bradykinin and other peptides, has the potential to provide the potent antihypertensive and cardioprotective benefits observed for nonselective dual ACE/NEP inhibitors, such as omapatrilat, without the increased risk of adverse effects. We have synthesized three 1-carboxy-3-phenylpropyl dipeptide inhibitors with nanomolar potency based on the previously reported C-domain selective ACE inhibitor lisinopril-tryptophan (LisW) to probe the structural requirements for potent dual cACE/NEP inhibition. Here we report the synthesis, enzyme kinetic data, and high-resolution crystal structures of these inhibitors bound to nACE and cACE, providing valuable insight into the factors driving potency and selectivity. Overall, these results highlight the importance of the interplay between the S' and S' subsites for ACE domain selectivity, providing guidance for future chemistry efforts toward the development of dual cACE/NEP inhibitors.

PubMed: 35113565
DOI: 10.1021/acs.jmedchem.1c01924

Experimental method

X-RAY DIFFRACTION (1.65 Å)