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

doi:10.1039/c9md00485h

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

RSC Med Chem. 2020 Jan 8;11(2):234-244. doi: 10.1039/c9md00485h. eCollection 2020 Feb 1.

Authors

Affiliations

¹ Department of Medicinal Chemistry , BMC , Uppsala University , P.O. Box 574 , SE-751 23 Uppsala , Sweden.
² Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences , Parkville , Victoria 3052 , Australia . Email: philip.thompson@monash.edu.
³ Department of Cell and Molecular Biology , BMC , Uppsala University , Box 596 , SE-751 24 Uppsala , Sweden.
⁴ The Beijer Laboratory , Department of Medicinal Chemistry , BMC , Uppsala University , P.O. Box 574 , SE-751 23 Uppsala , Sweden.
⁵ Biomedicine Discovery Institute , Department of Physiology , Monash University , Clayton , Victoria 3800 , Australia.
⁶ The Beijer Laboratory , Department of Pharmaceutical Biosciences , Division of Biological Research on Drug Dependence , BMC , Uppsala University , P.O. Box 591 , SE-751 24 Uppsala , Sweden.
⁷ Science for Life Laboratory , Department of Medicinal Chemistry , BMC , Uppsala University , SE-751 24 Uppsala , Sweden.

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.