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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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New ketomethylene inhibitor analogues: synthesis and assessment of structural determinants for N-domain selective inhibition of angiotensin-converting enzyme

Rajni K. Sharma1, a / Ross G. Douglas2, a / Stefan Louw1 / Kelly Chibale1 / 2

1Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, Faculty of Science, University of Cape Town, Rondebosch, Cape Town 7701, South Africa

2Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7935, South Africa

aThese authors contributed equally to the work.

Corresponding author

Citation Information: . Volume 393, Issue 6, Pages 485–493, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/hsz-2012-0127, June 2012

Publication History:


Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase containing two homologous domains. While the C-domain plays a major role in blood pressure regulation, the N-domain hydrolyzes the antifibrotic agent N-acetyl-Ser-Asp-Lys-Pro. Thus, N-domain selective (N-selective) inhibitors could be useful in the treatment of conditions relating to excessive tissue fibrosis. New keto-ACE analogues were designed that contained functionalities considered important for N-selective inhibitor RXP407 binding, namely, a P2 Asp, N-acetyl group, and C-terminal amide. Such functionalities were incorporated to assess the structural determinants for N-selective binding in a novel inhibitor template. Inhibitors containing a C-terminal amide and modified P2′ group were poor inhibitors of the N-domain, with several of these displaying improved inhibition of the C-domain. Molecules with both a C-terminal amide and P2 Asp were also poor inhibitors and not N-selective. Compounds containing a free C-terminus, a P2 Asp and protecting group displayed a change of more than 1000-fold N-selectivity compared with the parent molecule. Molecular docking models revealed interaction of these P2 groups with S2 residues Tyr369 and Arg381. This study emphasizes the importance of P2 functionalities in allowing for improved N-selective binding and provides further rationale for the design of N-selective inhibitors, which could be useful in treating tissue fibrosis.

Keywords: inhibitor design; kinetics; metallopeptidase; molecular docking; peptidomimetic inhibitors

Supplementary Article Materials

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