Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II.
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.
Laboratory of Molecular Biology, Medical Research Council , Cambridge CB2 0QH, United Kingdom.
Francesca
F
Magnani
Charalampos G
CG
Pappas
Tim
T
Crook
Vassiliki
V
Magafa
Paul
P
Cordopatis
Susumu
S
Ishiguro
Naomi
N
Ohta
Jana
J
Selent
Sanja
S
Bosnyak
Emma S
ES
Jones
Ioannis P
IP
Gerothanassis
Masaaki
M
Tamura
Robert E
RE
Widdop
Andreas G
AG
Tzakos
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II