2. Academic Validation
  3. Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition

Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition

  • J Med Chem. 2022 Feb 24;65(4):3371-3387. doi: 10.1021/acs.jmedchem.1c01924.
Lauren B Arendse 1 2,  Gyles E Cozier 3,  Charles J Eyermann 4,  Gregory S Basarab 4,  Sylva L Schwager 1 2,  Kelly Chibale 1 4 5 6,  K Ravi Acharya 3,  Edward D Sturrock 1 2
Affiliations

Affiliations

  • 1 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town 7925, South Africa.
  • 2 Department of Integrative Biomedical Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa.
  • 3 Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
  • 4 Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, Cape Town 7701, South Africa.
  • 5 Department of Chemistry, University of Cape Town, Rondebosch, Cape Town 7701, South Africa.
  • 6 South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, Cape Town 7701, South Africa.
PMID: 35113565 DOI: 10.1021/acs.jmedchem.1c01924
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 S1' and S2' subsites for ACE domain selectivity, providing guidance for future chemistry efforts toward the development of dual cACE/NEP inhibitors.

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