Binding to and inhibition of insulin-regulated aminopeptidase 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, Mathias Hallberg

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17 Citations (Scopus)

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 gamma-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-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.
Original languageEnglish
Pages (from-to)413-424
Number of pages12
JournalMolecular Pharmacology
Volume89
Issue number4
DOIs
Publication statusPublished - Apr 2016

Cite this

Diwakarla, S., Nylander, E., Gronbladh, A., Vanga, S. R., Khan, Y. S., Gutierrez-de-Teran, H., ... Hallberg, M. (2016). Binding to and inhibition of insulin-regulated aminopeptidase by macrocyclic disulfides enhances spine density. Molecular Pharmacology, 89(4), 413-424. https://doi.org/10.1124/mol.115.102533
Diwakarla, Shanti ; Nylander, Erik ; Gronbladh, Alfhild ; Vanga, Sudarsana Reddy ; Khan, Yasmin Shamsudin ; Gutierrez-de-Teran, Hugo ; Ng, Leelee ; Pham, Vi ; Savmarker, Jonas ; Lundback, Thomas ; Jenmalm-Jensen, Annika ; Andersson, Hanna ; Engen, Karin ; Rosenstrom, Ulrika ; Larhed, Mats ; Aqvist, Johan ; Chai, Siew Yeen ; Hallberg, Mathias. / Binding to and inhibition of insulin-regulated aminopeptidase by macrocyclic disulfides enhances spine density. In: Molecular Pharmacology. 2016 ; Vol. 89, No. 4. pp. 413-424.
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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 gamma-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-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.",
author = "Shanti Diwakarla and Erik Nylander and Alfhild Gronbladh and Vanga, {Sudarsana Reddy} and Khan, {Yasmin Shamsudin} and Hugo Gutierrez-de-Teran and Leelee Ng and Vi Pham and Jonas Savmarker and Thomas Lundback and Annika Jenmalm-Jensen and Hanna Andersson and Karin Engen and Ulrika Rosenstrom and Mats Larhed and Johan Aqvist and Chai, {Siew Yeen} and Mathias Hallberg",
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Diwakarla, S, Nylander, E, Gronbladh, A, Vanga, SR, Khan, YS, Gutierrez-de-Teran, H, Ng, L, Pham, V, Savmarker, J, Lundback, T, Jenmalm-Jensen, A, Andersson, H, Engen, K, Rosenstrom, U, Larhed, M, Aqvist, J, Chai, SY & Hallberg, M 2016, 'Binding to and inhibition of insulin-regulated aminopeptidase by macrocyclic disulfides enhances spine density', Molecular Pharmacology, vol. 89, no. 4, pp. 413-424. https://doi.org/10.1124/mol.115.102533

Binding to and inhibition of insulin-regulated aminopeptidase by macrocyclic disulfides enhances spine density. / Diwakarla, Shanti; Nylander, Erik; Gronbladh, Alfhild; Vanga, Sudarsana Reddy; Khan, Yasmin Shamsudin; Gutierrez-de-Teran, Hugo; Ng, Leelee; Pham, Vi; Savmarker, Jonas; Lundback, Thomas; Jenmalm-Jensen, Annika; Andersson, Hanna; Engen, Karin; Rosenstrom, Ulrika; Larhed, Mats; Aqvist, Johan; Chai, Siew Yeen; Hallberg, Mathias.

In: Molecular Pharmacology, Vol. 89, No. 4, 04.2016, p. 413-424.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Binding to and inhibition of insulin-regulated aminopeptidase by macrocyclic disulfides enhances spine density

AU - Diwakarla, Shanti

AU - Nylander, Erik

AU - Gronbladh, Alfhild

AU - Vanga, Sudarsana Reddy

AU - Khan, Yasmin Shamsudin

AU - Gutierrez-de-Teran, Hugo

AU - Ng, Leelee

AU - Pham, Vi

AU - Savmarker, Jonas

AU - Lundback, Thomas

AU - Jenmalm-Jensen, Annika

AU - Andersson, Hanna

AU - Engen, Karin

AU - Rosenstrom, Ulrika

AU - Larhed, Mats

AU - Aqvist, Johan

AU - Chai, Siew Yeen

AU - Hallberg, Mathias

PY - 2016/4

Y1 - 2016/4

N2 - 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 gamma-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-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.

AB - 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 gamma-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-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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/26769413

U2 - 10.1124/mol.115.102533

DO - 10.1124/mol.115.102533

M3 - Article

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EP - 424

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 1521-0111

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