β-Homo-amino Acid Scan of Angiotensin IV

Lukaszuk, Aneta; Demaegdt, Heidi; Szemenyei, Erzsébet; Tóth, Géza; Tymecka, Dagmara; Misicka, Aleksandra; Karoyan, Philippe; Vanderheyden, Patrick; Vauquelin, Georges; Tourwé, Dirk

doi:10.1021/jm701490g

Cited by 56 publications

(91 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Efforts were taken to develop AngIVderived IRAP inhibitors with improved selectivity versus AP-N and the AT 1 receptor, as well as resistance to proteolytic degradation. Lukaszuk et al, 2008) reported that the AngIV analog AL-11 (pK i 7.25 for IRAP enzyme activity) in which the b-homo amino acid b obtain AL-40 with a pK i is 8.07 for IRAP (Lukaszuk et al, 2009). Substitution of the latter Gly 5 by norvaline led to an analog (IVDE77) with further increased affinity (pK i is 8.77 for IRAP) Nikolaou et al, 2013).…”

Section: Pharmacology Of Angiv Analogsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

et al. 2015

View full text Add to dashboard Cite

Section: Pharmacology Of Angiv Analogsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

et al. 2015

View full text Add to dashboard Cite

“…Both potent and specific drug-like IRAP inhibitors (Borhade et al, 2014;Mountford et al, 2014), some with proven effects in vivo (Albiston et al, , 2011, and inhibitors with more peptidic character (Kobori et al, , 1998Wolfe, 2002;Axen et al, 2006;Axen et al, 2007;Andersson et al, 2008;Lukaszuk et al, 2008Lukaszuk et al, , 2009Hallberg, 2009) have been disclosed by us and others. We use an approach to discover efficient Ang IV peptidomimetics that relies on stepwise alterations of Ang IV by applying various cyclization procedures to restrict conformational flexibility and to allow determination of the bioactive conformation of Ang IV when it binds to IRAP (Axen et al, 2006(Axen et al, , 2007.…”

Section: Introductionmentioning

confidence: 93%

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

et al. 2016

View full text Add to dashboard Cite

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 g-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.

show abstract

“…In view of the potential impact of IRAP binding on the NF-κB pathway, 30,31 we investigated the modulatory activity of Ang IV and the stable Ang IV-analogue AL-11 33 on the expression of NF-κB regulated genes (inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor-necrosis factor α (TNFα), intercellular adhesion molecule 1 (ICAM-1)) in macrophages by quantitative real-time PCR (Table 1). None of these genes were induced by Ang IV or AL-11, suggesting that IRAP binding does not directly stimulate NF-κB signaling in macrophages ( Figure 11).…”

Section: Irap Ligands Do Not Modulate Nf-κb Regulated Gene Expressionmentioning

confidence: 99%

Presence and regulation of insulin-regulated aminopeptidase in mouse macrophages

Nikolaou

Stijlemans

Laoui

et al. 2014

J Renin Angiotensin Aldosterone Syst

Self Cite

View full text Add to dashboard Cite

Introduction: The insulin-regulated aminopeptidase (IRAP) is expressed in several cell types, where it is mainly located in specialized secretory endosomes that are quickly recruited to the cell surface upon cell type-specific activation. Here we describe for the first time the expression and subcellular distribution of IRAP in macrophages. Methods: IRAP mRNA expression, protein expression and presence at the cell surface was investigated by real-time polymerase chain reaction (PCR), Western blot and [³H]IVDE77 binding, respectively. Results: IRAP mRNA expression was increased by interferon-γ (IFN-γ) and lipopolysaccharide (LPS), but not by antiinflammatory cytokines (interleukin (IL)-4, IL-10, transforming growth factor β (TGF-β)). IFN-γ increased [³H]IVDE77 binding steadily over time, while LPS quickly and transiently recruited IRAP to the cell surface. Combined stimulations with IFN-γ and LPS showed the same pattern as LPS alone. Latex particles also induced a transient recruitment of IRAP to the cell surface, but no difference was observed in phagocytic uptake between wild-type and IRAP -/-macrophages, suggesting that the enzymatic activity of IRAP is not required for the ingestion of particles. Conclusion: IRAP is more highly expressed in pro-inflammatory M1-activated macrophages and its presence at the cell surface is modulated upon exposure to IFN-γ, LPS or exogenous particles.

show abstract

β-Homo-amino Acid Scan of Angiotensin IV

Cited by 56 publications

References 38 publications

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

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

Presence and regulation of insulin-regulated aminopeptidase in mouse macrophages

Contact Info

Product

Resources

About