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

Nicholas Barlow, Sudarsana Reddy Vanga, Jonas Sävmarker, Anja Sandström, Peta Burns, Anders Hallberg, Johan Åqvist, Hugo Gutiérrez-De-Terán, Mathias Hallberg, Mats Larhed, Siew Yeen Chai, Philip E. Thompson

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5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)234-244
Number of pages11
JournalRSC Medicinal Chemistry
Volume11
Issue number2
DOIs
Publication statusPublished - Feb 2020

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