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

Francesca Magnani, Charalampos G Pappas, Tim Crook, Vassiliki Magafa, Paul A Cordopatis, Susumu Ishiguro, Naomi Ohta, Jana Selent, Sanja Bosnyak, Emma S Jones, Ioannis P Gerothanassis, Masaaki Tamura, Robert E Widdop, Andreas G Tzakos

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)1420 - 1425
Number of pages6
JournalACS Chemical Biology
Volume9
Issue number7
DOIs
Publication statusPublished - 2014

Cite this

Magnani, F., Pappas, C. G., Crook, T., Magafa, V., Cordopatis, P. A., Ishiguro, S., ... Tzakos, A. G. (2014). Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II. ACS Chemical Biology, 9(7), 1420 - 1425. https://doi.org/10.1021/cb500063y
Magnani, Francesca ; Pappas, Charalampos G ; Crook, Tim ; Magafa, Vassiliki ; Cordopatis, Paul A ; Ishiguro, Susumu ; Ohta, Naomi ; Selent, Jana ; Bosnyak, Sanja ; Jones, Emma S ; Gerothanassis, Ioannis P ; Tamura, Masaaki ; Widdop, Robert E ; Tzakos, Andreas G. / Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II. In: ACS Chemical Biology. 2014 ; Vol. 9, No. 7. pp. 1420 - 1425.
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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.",
author = "Francesca Magnani and Pappas, {Charalampos G} and Tim Crook and Vassiliki Magafa and Cordopatis, {Paul A} and Susumu Ishiguro and Naomi Ohta and Jana Selent and Sanja Bosnyak and Jones, {Emma S} and Gerothanassis, {Ioannis P} and Masaaki Tamura and Widdop, {Robert E} and Tzakos, {Andreas G}",
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Magnani, F, Pappas, CG, Crook, T, Magafa, V, Cordopatis, PA, Ishiguro, S, Ohta, N, Selent, J, Bosnyak, S, Jones, ES, Gerothanassis, IP, Tamura, M, Widdop, RE & Tzakos, AG 2014, 'Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II', ACS Chemical Biology, vol. 9, no. 7, pp. 1420 - 1425. https://doi.org/10.1021/cb500063y

Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II. / Magnani, Francesca; Pappas, Charalampos G; Crook, Tim; Magafa, Vassiliki; Cordopatis, Paul A; Ishiguro, Susumu; Ohta, Naomi; Selent, Jana; Bosnyak, Sanja; Jones, Emma S; Gerothanassis, Ioannis P; Tamura, Masaaki; Widdop, Robert E; Tzakos, Andreas G.

In: ACS Chemical Biology, Vol. 9, No. 7, 2014, p. 1420 - 1425.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II

AU - Magnani, Francesca

AU - Pappas, Charalampos G

AU - Crook, Tim

AU - Magafa, Vassiliki

AU - Cordopatis, Paul A

AU - Ishiguro, Susumu

AU - Ohta, Naomi

AU - Selent, Jana

AU - Bosnyak, Sanja

AU - Jones, Emma S

AU - Gerothanassis, Ioannis P

AU - Tamura, Masaaki

AU - Widdop, Robert E

AU - Tzakos, Andreas G

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Magnani F, Pappas CG, Crook T, Magafa V, Cordopatis PA, Ishiguro S et al. Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II. ACS Chemical Biology. 2014;9(7):1420 - 1425. https://doi.org/10.1021/cb500063y