Imperial College London
Alternate

DrRichardPerryman

Faculty of Medicine, Department of Brain Sciences

Research Associate
 
 
 
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Contact

 

r.perryman13 Website

 
 
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Location

 

E5Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Perryman:2023:10.1073/pnas.2116289119,
author = {Perryman, R and Renziehausen, A and Shaye, H and Kostagianni, AD and Tsiailanis, AD and Thorne, T and Chatziathanasiadou, MV and Sivolapenko, GB and El, Mubarak MA and Won, Han G and Zarzycka, B and Katritch, V and Lebon, G and Nigro, CL and Lattanzio, L and Morse, S and Choi, J and ONeill, K and Kanaki, Z and Klinakis, A and Crook, T and Cherezov, V and Tzakos, A and Syed, N},
doi = {10.1073/pnas.2116289119},
journal = {Proceedings of the National Academy of Sciences of USA},
title = {Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma},
url = {http://dx.doi.org/10.1073/pnas.2116289119},
volume = {119},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a novel therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G protein or β-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2 tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation and increased levels of apoptosis in an orthotopic xenograft model of GBM.
AU  - Perryman,R
AU  - Renziehausen,A
AU  - Shaye,H
AU  - Kostagianni,AD
AU  - Tsiailanis,AD
AU  - Thorne,T
AU  - Chatziathanasiadou,MV
AU  - Sivolapenko,GB
AU  - El,Mubarak MA
AU  - Won,Han G
AU  - Zarzycka,B
AU  - Katritch,V
AU  - Lebon,G
AU  - Nigro,CL
AU  - Lattanzio,L
AU  - Morse,S
AU  - Choi,J
AU  - ONeill,K
AU  - Kanaki,Z
AU  - Klinakis,A
AU  - Crook,T
AU  - Cherezov,V
AU  - Tzakos,A
AU  - Syed,N
DO  - 10.1073/pnas.2116289119
PY  - 2023///
SN  - 0027-8424
TI  - Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma
T2  - Proceedings of the National Academy of Sciences of USA
UR  - http://dx.doi.org/10.1073/pnas.2116289119
UR  - https://www.pnas.org/doi/full/10.1073/pnas.2116289119
UR  - http://hdl.handle.net/10044/1/97836
VL  - 119
ER  -
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