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

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

doi:10.1021/cb500063y

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

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

Research output: Contribution to journal › Article › peer-review

28 Citations (Scopus)

207 Downloads (Pure)

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 (K_i = 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 language	English
Pages (from-to)	1420-1425
Number of pages	6
Journal	ACS Chemical Biology
Volume	9
Issue number	7
DOIs	https://doi.org/10.1021/cb500063y
Publication status	Published - 18 Jul 2014

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SDG 3 Good Health and Well-being

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10.1021/cb500063y

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© 2014 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 2.12 MBLicence: CC BY

http://pubs.acs.org/journal/acbcct

Cite this

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title = "Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II",

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 Paul Cordopatis 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.\}",

year = "2014",

month = jul,

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doi = "10.1021/cb500063y",

language = "English",

volume = "9",

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TY - JOUR

T1 - Electronic sculpting of ligand-GPCR subtype selectivity

T2 - the case of angiotensin II

AU - Magnani, Francesca

AU - Pappas, Charalampos G.

AU - Crook, Tim

AU - Magafa, Vassiliki

AU - Cordopatis, Paul

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.

PY - 2014/7/18

Y1 - 2014/7/18

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84904577699

U2 - 10.1021/cb500063y

DO - 10.1021/cb500063y

M3 - Article

C2 - 24787922

AN - SCOPUS:84904577699

SN - 1554-8929

VL - 9

SP - 1420

EP - 1425

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 7

ER -

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

Abstract

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