[3H]IVDE77, a novel radioligand with high affinity and selectivity for the insulin-regulated aminopeptidase

Alexandros Nikolaou, Isabelle Van den Eynde, Dirk Tourwé, Georges Vauquelin, Géza Tóth, Jayapal Reddy Mallareddy, Marko Poglitsch, Jo A Van Ginderachter, Patrick M L Vanderheyden

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

The hexapeptide angiotensin IV (Ang IV) induces diverse biological effects such as memory enhancement and protection against ischemic stroke. Studies on the mechanism of Ang IV however are hampered by its instability and its lack of selectivity. The high-affinity binding site for Ang IV is the insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3), but Ang IV also acts as a weak agonist for the Ang II-receptor (AT1), implying the need for stable and highly selective Ang IV-analogues. Here we present the screening of novel Ang IV-analogues, selected on basis of high affinity for IRAP, high selectivity (compared to aminopeptidase N and the AT1 receptor) and resistance against proteases. The selected compound IVDE77 possesses a number of advantages compared to Ang IV: (i) it has a 40 times higher affinity for IRAP (Ki 1.71 nM), (ii) it does not activate the AT1 receptor, (iii) it is easily radiolabeled with tritium and (iv) it is resistant to proteolysis, even in human plasma. In addition, pre-treatment of intact CHO-K1 cells with IVDE77 led to a virtually complete inhibition of subsequent intracellular accumulation of [(3)H]IVDE77-IRAP complexes. IVDE77 thus represents the first Ang IV-analogue able to abolish IRAP-availability completely at the cell surface in vitro. In summary, IVDE77 is a useful tool for the detection of IRAP under physiological conditions, and may contribute to elucidating the mechanism of Ang IV to ascertain which functions are IRAP-dependent.

Original languageEnglish
Pages (from-to)93-102
Number of pages10
JournalEuropean Journal of Pharmacology
Volume702
Issue number1-3
DOIs
Publication statusPublished - 28 Feb 2013

Keywords

  • Angiotensin II
  • Animals
  • Azepines
  • Binding, Competitive
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Cystinyl Aminopeptidase
  • HEK293 Cells
  • Humans
  • Ligands
  • Oligopeptides
  • Research Support, Non-U.S. Gov't

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