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Molecular Pharmacology

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Research ArticleArticle

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

Shanti Diwakarla, Erik Nylander, Alfhild Gronbladh, Sudarsana Reddy Vanga, Yasmin Shamsudin Khan, Hugo Gutierrez-de-Teran, Leelee Ng, Vi Pham, Jonas Savmarker, Thomas Lundback, Annika Jenmalm-Jensen, Hanna Andersson, Karin Engen, Ulrika Rosenstrom, Mats Larhed, Johan Aqvist, Siew Yeen Chai and Mathias Hallberg
Molecular Pharmacology January 14, 2016, mol.115.102533; DOI: https://doi.org/10.1124/mol.115.102533
Shanti Diwakarla
1 Uppsala University;
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Erik Nylander
1 Uppsala University;
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Alfhild Gronbladh
1 Uppsala University;
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Sudarsana Reddy Vanga
1 Uppsala University;
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Yasmin Shamsudin Khan
1 Uppsala University;
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Hugo Gutierrez-de-Teran
1 Uppsala University;
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Leelee Ng
2 Monash University;
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Vi Pham
2 Monash University;
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Jonas Savmarker
1 Uppsala University;
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Thomas Lundback
3 Karolinska Institute
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Annika Jenmalm-Jensen
3 Karolinska Institute
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Hanna Andersson
1 Uppsala University;
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Karin Engen
1 Uppsala University;
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Ulrika Rosenstrom
1 Uppsala University;
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Mats Larhed
1 Uppsala University;
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Johan Aqvist
1 Uppsala University;
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Siew Yeen Chai
2 Monash University;
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Mathias Hallberg
1 Uppsala University;
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Abstract

Angiotensin IV (Ang IV) and related peptide analogues, as well as non-peptide 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 macrocylic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N-terminal 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-terminal to human IRAP were predicted by docking and molecular dynamics (MD) simulations. The binding free energies calculated with the linear interaction energy (LIE) 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-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.

  • Molecular dynamics
  • Structure-activity relationships and modeling
  • Immunocytochemistry
  • Neuropeptides, peptidases
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 104 (6)
Molecular Pharmacology
Vol. 104, Issue 6
1 Dec 2023
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Research ArticleArticle

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

Shanti Diwakarla, Erik Nylander, Alfhild Gronbladh, Sudarsana Reddy Vanga, Yasmin Shamsudin Khan, Hugo Gutierrez-de-Teran, Leelee Ng, Vi Pham, Jonas Savmarker, Thomas Lundback, Annika Jenmalm-Jensen, Hanna Andersson, Karin Engen, Ulrika Rosenstrom, Mats Larhed, Johan Aqvist, Siew Yeen Chai and Mathias Hallberg
Molecular Pharmacology January 14, 2016, mol.115.102533; DOI: https://doi.org/10.1124/mol.115.102533

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Research ArticleArticle

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

Shanti Diwakarla, Erik Nylander, Alfhild Gronbladh, Sudarsana Reddy Vanga, Yasmin Shamsudin Khan, Hugo Gutierrez-de-Teran, Leelee Ng, Vi Pham, Jonas Savmarker, Thomas Lundback, Annika Jenmalm-Jensen, Hanna Andersson, Karin Engen, Ulrika Rosenstrom, Mats Larhed, Johan Aqvist, Siew Yeen Chai and Mathias Hallberg
Molecular Pharmacology January 14, 2016, mol.115.102533; DOI: https://doi.org/10.1124/mol.115.102533
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