Development of potent and selective phosphinic peptide inhibitors of angiotensin-converting enzyme 2.

Abstract:

:Angiotensin-converting enzyme 2 (ACE2), a recently identified human homologue of angiotensin-converting enzyme, is a zinc metallocarboxypeptidase which may play a unique role in cardiovascular and renal function. Here we report the discovery of potent and selective inhibitors of ACE2, which have been identified by evaluating a series of phosphinic di- and tripeptides of the general formula: Z-Xaa(PO 2-CH 2)YaaOH and Ac-Zaa-Xaa(PO 2-CH 2)YaaOH. The most potent inhibitor in this series is a tripeptide that displays a K i value of 0.4 nM toward ACE2 and is 3 orders of magnitude less potent toward carboxypeptidase A. Phosphinic tripeptides exhibit high potency exclusively when the Xaa position is occupied by a pseudoproline. A model of interaction between one inhibitor of this series and ACE2 suggests that the critical role played by a proline in inhibitors, but also for substrates hydrolysis, may rely on the presence of Tyr (510) in the ACE2 active site.

journal_name

J Med Chem

authors

Mores A,Matziari M,Beau F,Cuniasse P,Yiotakis A,Dive V

doi

10.1021/jm701275z

subject

Has Abstract

pub_date

2008-04-10 00:00:00

pages

2216-26

issue

7

eissn

0022-2623

issn

1520-4804

journal_volume

51

pub_type

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