Jump to main content
Jump to site search


Macrocyclic peptidomimetics as inhibitors of insulin-regulated aminopeptidase (IRAP)

Author affiliations

Abstract

Macrocyclic analogues of the linear hexapeptide, angiotensin IV (AngIV) have proved to be potent inhibitors of insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 3.4.11.3). Along with higher affinity, macrocycles may also offer better metabolic stability, membrane permeability and selectivity, however predicting the outcome of particular cycle modifications is challenging. Here we describe the development of a series of macrocyclic IRAP inhibitors with either disulphide, olefin metathesis or lactam bridges and variations of ring size and other functionality. The binding mode of these compounds is proposed based on molecular dynamics analysis. Estimation of binding affinities (ΔG) and relative binding free energies (ΔΔG) with the linear interaction energy (LIE) method and free energy perturbation (FEP) method showed good general agreement with the observed inhibitory potency. Experimental and calculated data highlight the cumulative importance of an intact N-terminal peptide, the specific nature of the macrocycle, the phenolic oxygen and the C-terminal functionality.

Graphical abstract: Macrocyclic peptidomimetics as inhibitors of insulin-regulated aminopeptidase (IRAP)

Back to tab navigation

Supplementary files

Article information


Submitted
15 Oct 2019
Accepted
21 Nov 2019
First published
08 Jan 2020

RSC Med. Chem., 2020, Advance Article
Article type
Research Article

Macrocyclic peptidomimetics as inhibitors of insulin-regulated aminopeptidase (IRAP)

N. Barlow, S. R. Vanga, J. Sävmarker, A. Sandström, P. Burns, A. Hallberg, J. Åqvist, H. Gutiérrez-de-Terán, M. Hallberg, M. Larhed, S. Y. Chai and P. E. Thompson, RSC Med. Chem., 2020, Advance Article , DOI: 10.1039/C9MD00485H

Social activity

Search articles by author

Spotlight

Advertisements