Identification of Apj receptor agonists and antagonists

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Pulmonary arterial hypertension (PAH) is a life-threatening elevation of blood pressure which can lead to heart failure. Across the world, the cases of PAH are in the range of 100-200k per year. There are currently no good medicines for treatment of PAH. Consequently, there is a need for new therapies.The apelin receptor is a promising new target for treatment of PAH. There is strong published evidence that an apelin receptor agonist would offer disease therapy. Specifically, we would be interested in the development of a so-called 'biased' receptor agonist. Published data suggests that a biased agonist would generate a therapeutic effect without toxic side effects.Objectives:Identify an apelin receptor agonist using molecular modelling, biological screening & medicinal chemistry.Optimise the agonist for properties consistent with an orally delivered drug.Investigate through molecular modelling and chemical synthesis the importance of receptor bias in understanding the action of the agonist at the receptor.Identify and optimize an antagonist of the apelin receptor.The project is highly cross disciplinary and will involve development of skills in a number of areas, including synthetic chemistry, molecular modelling and biological screening of relevance to treatment of PAH. Initially, the published apelin receptor agonists will be investigated to develop a computational model for prediction of agonist binding to the receptor. The model will be used to guide the design of new agonists. As yet no published agonists have been shown to demonstrate receptor bias. Our intention will be to understand the origin of bias by molecular modelling to guide the design of the first receptor biased agonist. A significant aim of the project will be optimise the new agonists for so-called 'drug-like' properties. Agonists will be optimised by medicinal chemistry approaches using rounds of synthetic chemistry and biological screening for improvement in potency, selectivity and properties consistent with a 'drug-like' compound. Selected agonists will be assessed for effectiveness in rat models for PAH available in a collaborator's lab at the University of Cambridge. The intention is to identify a potent and selective biased agonist with potential for development into a therapeutic. The origin of receptor bias will be investigated by use of mutagenesis studies (a technique which should allow for analysis of the importance of specific areas of the receptor for conferring bias). Understanding the origin of receptor bias will allow us to develop more potent and more selective (less toxic) agonists.