Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density

Molecular Pharmacology
Shanti DiwakarlaMathias Hallberg

Abstract

Angiotensin IV (Ang IV) and related peptide analogs, as well as nonpeptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocyclic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N terminus of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09, and of Ang IV in either the extended or γ-turn conformation at the C terminus to human IRAP were predicted by docking and molecular dynamics simulations. The binding free energies calculated with the linear interaction energy method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fol...Continue Reading

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Citations

Apr 15, 2016·Assay and Drug Development Technologies·Karin EngenMats Larhed
Jan 12, 2017·The FEBS Journal·Nyssa DrinkwaterSheena McGowan
Jun 14, 2017·Medicinal Research Reviews·Mathias HallbergAnders Hallberg
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Nov 13, 2020·Frontiers in Pharmacology·Mathias Hallberg, Mats Larhed
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Apr 20, 2021·Frontiers in Molecular Biosciences·Sudarsana Reddy VangaHugo Gutiérrez-de-Terán
May 11, 2021·Frontiers in Molecular Biosciences·Siew Yeen ChaiEfstratios Stratikos
Jul 20, 2018·ACS Omega·Sudarsana Reddy VangaHugo Gutiérrez-de-Terán
Jul 18, 2020·ACS Medicinal Chemistry Letters·Anastasia MpakaliEfstratios Stratikos

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