Publications

@article{Harwood2025-cz,

title = {Agonist efficacy at the β2AR is driven by the faster  association rate of the Gs protein},

author = {Clare R Harwood and David A Sykes and Theo Redfern-Nichols and Owen Underwood and Colin Nicholson and Armin N Khoshgrudi and Eline J Koers and Graham Ladds and Stephen J Briddon and Dmitry B Veprintsev},

doi = {10.3389/fphar.2025.1367991},

year  = {2025},

date = {2025-03-01},

urldate = {2025-03-01},

journal = {Front. Pharmacol.},

volume = {16},

pages = {1367991},

publisher = {Frontiers Media SA},

abstract = {Introduction: The β2-adrenoceptor (β2AR) is a class 

 A G protein-coupled receptor (GPCR). It is therapeutically 

 relevant in asthma and chronic obstructive pulmonary disease 

 (COPD), where β2AR agonists relieve bronchoconstriction. 

 The β2AR is a prototypical GPCR for structural and 

 biophysical studies. However, the molecular basis of agonist 

 efficacy at the β2AR is not understood. We hypothesised 

 that the kinetics of GPCR-G protein interactions could play a 

 role in determining ligand efficacy. By studying a range of 

 agonists with varying efficacy, we examined the relationship 

 between ligand-induced mini-Gs binding to the β2AR and 

 ligand efficacy, along with the ability of individual ligands to 

 activate the G protein in cells. Methods: We used NanoBRET 

 technology to measure ligand-induced binding of purified 

 Venus-mini-Gs to β2AR-nLuc in membrane preparations under 

 both equilibrium and kinetic conditions. In addition, we 

 examined the ability of these β2AR agonists to activate 

 the heterotrimeric Gs protein, measured using the Gs-CASE 

 protein biosensor in living cells. This assay detects a 

 reduction in NanoBRET between the nano-luciferase (nLuc) donor 

 on the Gα subunit and Venus acceptor on the Gγ 

 upon Gs protein activation. Results: The 12 β2AR agonists 

 under study revealed a broad range of ligand potency and 

 efficacy values in the cellular Gs-CASE assays. Kinetic 

 characterisation of mini-Gs binding to the agonist β2AR 

 complex revealed a strong correlation between ligand efficacy 

 values (Emax) and mini-Gs affinity (K d) and its association 

 rate (k on). In contrast, there was no correlation between 

 ligand efficacy and reported ligand dissociation rates (or 

 residence times). Conclusion: The association rate (k on) of the 

 G protein to the agonist β2AR complex is directly 

 correlated with ligand efficacy. These data support a model in 

 which higher-efficacy agonists induce the β2AR to adopt a 

 conformation that is more likely to recruit G protein. 

 Conversely, these data did not support the role of agonist 

 binding kinetics in determining the molecular basis of efficacy.},

keywords = {association   rate kon, dissociation rate koff, efficacy, G protein-coupled receptor, kinetics, β2-adrenoceptor},

pubstate = {published},

tppubtype = {article}

}

@article{Panos2023-mp,

title = {Faricimab: Transforming the future of macular diseases treatment 

 - A comprehensive review of clinical studies},

author = {Georgios D Panos and Arun Lakshmanan and Panagiotis Dadoukis and Matteo Ripa and Lorenzo Motta and Winfried M Amoaku},

year  = {2023},

date = {2023-09-01},

journal = {Drug Des. Devel. Ther.},

volume = {17},

pages = {2861\textendash2873},

publisher = {Informa UK Limited},

abstract = {Degenerative eye conditions such as age-related macular 

 degeneration (AMD), diabetic retinopathy, and retinal vein 

 occlusion are major contributors to significant vision loss in 

 developed nations. The primary therapeutic approach for managing 

 complications linked to these diseases involves the intravitreal 

 delivery of anti-vascular endothelial growth factor (VEGF) 

 treatments. Faricimab is a novel, humanised, bispecific antibody 

 that simultaneously binds all VEGF-A isoforms and 

 Angiopoietin-2, which has been approved by regulatory agencies, 

 such as the US Food and Drug Administration (FDA), the UK 

 Medicines and Healthcare products Regulatory Agency (MHRA) and 

 the European Medicines Agency (EMA), for the treatment of 

 neovascular AMD and diabetic macular oedema (DMO). Intravitreal 

 faricimab holds the promise of reducing the treatment burden for 

 patients with these conditions by achieving comparable or 

 superior therapeutic outcomes with fewer clinic visits. The 

 scope of faricimab's application includes addressing complex 

 macular conditions such as DMO. This review intends to elucidate 

 the distinctive pharmacological characteristics of faricimab and 

 provide an overview of the key clinical trials and real-world 

 studies that assess its effectiveness and safety in treating 

 degenerative macular diseases.},

keywords = {age-related macular degeneration, anti-VEGF, degenerative   macular disorders, diabetic   retinopathy, diabetic macular oedema, efficacy, faricimab, intravitreal treatment, retinal vein occlusion, safety},

pubstate = {published},

tppubtype = {article}

}