Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II
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- dc.contributor.author Magnani, Francesca
- dc.contributor.author Pappas, Charalampos G.
- dc.contributor.author Crook, Tim
- dc.contributor.author Magafa, Vassiliki
- dc.contributor.author Cordopatis, Paul
- dc.contributor.author Ishiguro, Susumu
- dc.contributor.author Ohta, Naomi
- dc.contributor.author Selent, Jana
- dc.contributor.author Bosnyak, Sanja
- dc.contributor.author Jones, Emma S.
- dc.contributor.author Gerothanassis, Ioannis P.
- dc.contributor.author Tamura, Masaaki
- dc.contributor.author Widdop, Robert E.
- dc.contributor.author Tzakos, Andreas G.
- dc.date.accessioned 2024-01-16T06:54:03Z
- dc.date.available 2024-01-16T06:54:03Z
- dc.date.issued 2014
- dc.description.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.
- dc.format.mimetype application/pdf
- dc.identifier.citation Magnani F, Pappas CG, Crook T, Magafa V, Cordopatis P, Ishiguro S, et al. Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II. ACS Chem Biol. 2014 Apr 30;9(7):1420-5. DOI: 10.1021/cb500063y
- dc.identifier.doi http://dx.doi.org/10.1021/cb500063y
- dc.identifier.issn 1554-8929
- dc.identifier.uri http://hdl.handle.net/10230/58699
- dc.language.iso eng
- dc.publisher American Chemical Society (ACS)
- dc.relation.ispartof ACS Chemical Biology. 2014 Apr 30;9(7):1420-5
- dc.rights 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.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/deed.es
- dc.subject.other Angiotensina II
- dc.subject.other Medicaments
- dc.subject.other Càncer
- dc.title Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion