Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures

Shanti Diwakarla, Erik Nylander, Alfhild Grönbladh, Sudarsana Reddy Vanga, Yasmin Shamsudin Khan, Hugo Gutiérrez-De-Terán, Jonas Sävmarker, Leelee Ng, Vi Pham, Thomas Lundbäck, Annika Jenmalm-Jensen, Richard Svensson, Per Artursson, Sofia Zelleroth, Karin Engen, Ulrika Rosenström, Mats Larhed, Johan Åqvist, Siew Yeen Chai, Mathias Hallberg

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18 Citations (Scopus)

Abstract

The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of IRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug-like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors. A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.

Original languageEnglish
Pages (from-to)1383-1392
Number of pages10
JournalACS Chemical Neuroscience
Volume7
Issue number10
DOIs
Publication statusPublished - 19 Oct 2016

Keywords

  • aryl sulfonamides
  • dendritic spines
  • hippocampal neurons
  • Insulin-regulated aminopeptidase
  • ligand interaction energy simulations
  • molecular dynamics

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