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Title: The identification and pharmacological characterisation of novel apelin receptor agonists in vitro and in vivo
Author: Read, Cai
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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The apelin system is an evolving transmitter system consisting of the G protein coupled apelin receptor and two endogenous peptide ligands, apelin and elabela. It is implicated as a potential therapeutic for a number of diseases; however, the endogenous peptides are limited by half-life and bioavailability. This study aims to identify and pharmacologically characterise apelin agonists in vitro and in vivo and to evaluate their therapeutic potential in pulmonary arterial hypertension as a model disease. CMF-019 was identified as the first G protein biased apelin agonist. To date, suitable small molecule apelin agonists as experimental tool compounds have been limited and CMF-019 represents an important advance. CMF-019 was active in vivo, producing an increase in cardiac contractility and vasodilatation, similar to apelin. These effects were achieved without receptor desensitisation, supporting the remarkable G protein bias observed in vitro. Furthermore, it was disease-modifying in vitro in an endothelial cell apoptosis assay but despite this, did not prevent pulmonary arterial hypertension in a monocrotaline rat model of the disease. An apelin mimetic peptide possessing an unnatural amino acid, MM202, conjugated chemically via a polyethylene glycol linker to an anti-serum domain antibody (AlbudAb) was also characterised. The product MM202-AlbudAb represents the first time an AlbudAb has been conjugated chemically to an unnatural peptide mimetic, providing protection from proteolysis and glomerular filtration. Importantly, it retained binding to albumin and demonstrated in vitro and in vivo activity at the apelin receptor. In conclusion, this thesis has identified and pharmacologically characterised two novel apelin agonists that possess significant advantages over the endogenous peptides. CMF-019 is suitable as an experimental tool compound and, as the first G protein biased small molecule, provides a starting point for more suitable therapeutics. In addition, MM202-AlbudAb proves that unnatural peptides can be conjugated to AlbudAb, supporting use of this technology in other small-peptide ligand transmitter systems.
Supervisor: Davenport, Anthony Peter Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Ligand bias ; Apelin Receptor ; G protein coupled receptor ; Cardiovascular pharmacology ; Pulmonary arterial hypertension