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Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II.

Magnani F, Pappas CG, Crook T, Magafa V, Cordopatis P, Ishiguro S, Ohta N, Selent J, Bosnyak S, Jones ES, Gerothanassis IP, Tamura M, Widdop RE, Tzakos AG - ACS Chem. Biol. (2014)

Bottom Line: This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target.We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions.Through this strategy an AT2R high affinity (Ki = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, Medical Research Council , Cambridge CB2 0QH, United Kingdom.

ABSTRACT
GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (Ki = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range.

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3D model of the AII–AT1R complex and the electronictuningstrategy used in this work for AII. (a) Key interactions between thehormone AII (yellow stick and surface) and AT1R (gray stick), comprisinghydrogen bonds (red dashed line) and hydrophobic contacts (green dashedline). (b) Conserved regions between AT1R and AT2R depicted in graystick and surface; unconserved regions are highlighted in a red stickrepresentation. ECL1, ECL2 correspond to the extracellular loops 1and 2 and TM2, 4, 5, and 6 correspond to transmembrane regions 2,4, 5, and 6, respectively. (c) The sequence of the hormone AII withits C-terminus highlighted. (d,e) The H6 of AII was alteredin this work with 4-X substituted phenylalanine on the frame of anelectronic strategy to regulate the compactness of the AII C-terminus.In (d) electron-rich aromatic residues stabilize the aromatic-prolylinteractions and lead to compactness,18 and in (e) electron-deficient aromatic residues result in less favorablearomatic-prolyl interactions and relatively reduced compactness.
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fig1: 3D model of the AII–AT1R complex and the electronictuningstrategy used in this work for AII. (a) Key interactions between thehormone AII (yellow stick and surface) and AT1R (gray stick), comprisinghydrogen bonds (red dashed line) and hydrophobic contacts (green dashedline). (b) Conserved regions between AT1R and AT2R depicted in graystick and surface; unconserved regions are highlighted in a red stickrepresentation. ECL1, ECL2 correspond to the extracellular loops 1and 2 and TM2, 4, 5, and 6 correspond to transmembrane regions 2,4, 5, and 6, respectively. (c) The sequence of the hormone AII withits C-terminus highlighted. (d,e) The H6 of AII was alteredin this work with 4-X substituted phenylalanine on the frame of anelectronic strategy to regulate the compactness of the AII C-terminus.In (d) electron-rich aromatic residues stabilize the aromatic-prolylinteractions and lead to compactness,18 and in (e) electron-deficient aromatic residues result in less favorablearomatic-prolyl interactions and relatively reduced compactness.

Mentions: However, significant challenges are posed for the rational designof GPCR subtype-selective ligands due to the high sequence conservationwithin the receptor subfamily.3 Indeed,in the absence of detailed knowledge of ligand–receptor recognitioninteractions for AT2R, identification of AT2R-selective ligands cameafter long and delicate synthetic efforts.10,14 Here, we describe a strategy to fine-tune ligand selectivity forthe AT2R/AT1R subtypes through electronic control of ligand aromatic-prolylinteractions (Figure 1). On the basis of thisstrategy, a highly AT2R-selective (18,000-fold higher selectivity(IC50AT1R/IC50AT2R)) and high affinity agonistanalogue (Ki = 3 nM) that exerted antiproliferativeactivity against MCF-7 breast carcinoma cells was obtained, pointingto a rational way to generate highly receptor subtype-selective drugs.


Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II.

Magnani F, Pappas CG, Crook T, Magafa V, Cordopatis P, Ishiguro S, Ohta N, Selent J, Bosnyak S, Jones ES, Gerothanassis IP, Tamura M, Widdop RE, Tzakos AG - ACS Chem. Biol. (2014)

3D model of the AII–AT1R complex and the electronictuningstrategy used in this work for AII. (a) Key interactions between thehormone AII (yellow stick and surface) and AT1R (gray stick), comprisinghydrogen bonds (red dashed line) and hydrophobic contacts (green dashedline). (b) Conserved regions between AT1R and AT2R depicted in graystick and surface; unconserved regions are highlighted in a red stickrepresentation. ECL1, ECL2 correspond to the extracellular loops 1and 2 and TM2, 4, 5, and 6 correspond to transmembrane regions 2,4, 5, and 6, respectively. (c) The sequence of the hormone AII withits C-terminus highlighted. (d,e) The H6 of AII was alteredin this work with 4-X substituted phenylalanine on the frame of anelectronic strategy to regulate the compactness of the AII C-terminus.In (d) electron-rich aromatic residues stabilize the aromatic-prolylinteractions and lead to compactness,18 and in (e) electron-deficient aromatic residues result in less favorablearomatic-prolyl interactions and relatively reduced compactness.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4374176&req=5

fig1: 3D model of the AII–AT1R complex and the electronictuningstrategy used in this work for AII. (a) Key interactions between thehormone AII (yellow stick and surface) and AT1R (gray stick), comprisinghydrogen bonds (red dashed line) and hydrophobic contacts (green dashedline). (b) Conserved regions between AT1R and AT2R depicted in graystick and surface; unconserved regions are highlighted in a red stickrepresentation. ECL1, ECL2 correspond to the extracellular loops 1and 2 and TM2, 4, 5, and 6 correspond to transmembrane regions 2,4, 5, and 6, respectively. (c) The sequence of the hormone AII withits C-terminus highlighted. (d,e) The H6 of AII was alteredin this work with 4-X substituted phenylalanine on the frame of anelectronic strategy to regulate the compactness of the AII C-terminus.In (d) electron-rich aromatic residues stabilize the aromatic-prolylinteractions and lead to compactness,18 and in (e) electron-deficient aromatic residues result in less favorablearomatic-prolyl interactions and relatively reduced compactness.
Mentions: However, significant challenges are posed for the rational designof GPCR subtype-selective ligands due to the high sequence conservationwithin the receptor subfamily.3 Indeed,in the absence of detailed knowledge of ligand–receptor recognitioninteractions for AT2R, identification of AT2R-selective ligands cameafter long and delicate synthetic efforts.10,14 Here, we describe a strategy to fine-tune ligand selectivity forthe AT2R/AT1R subtypes through electronic control of ligand aromatic-prolylinteractions (Figure 1). On the basis of thisstrategy, a highly AT2R-selective (18,000-fold higher selectivity(IC50AT1R/IC50AT2R)) and high affinity agonistanalogue (Ki = 3 nM) that exerted antiproliferativeactivity against MCF-7 breast carcinoma cells was obtained, pointingto a rational way to generate highly receptor subtype-selective drugs.

Bottom Line: This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target.We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions.Through this strategy an AT2R high affinity (Ki = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, Medical Research Council , Cambridge CB2 0QH, United Kingdom.

ABSTRACT
GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (Ki = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range.

Show MeSH
Related in: MedlinePlus