Exploiting formyl peptide receptors as a novel pharmacotherapy for pulmonary hypertension
Pulmonary hypertension (PH) is an incurable pulmonary vasculopathy for which the efficacy of currently used drugs is extremely poor. Available therapeutics (e.g. sildenafil) improve quality of life but survival rate remains at <50% over 5 years. The GPCRs, formyl peptide receptors (FPRs), which are integral to the regulation and resolution of inflammation, have recently attracted attention as potential therapeutic targets for cardiovascular disorders, but conventional FPR activation leads to both pro- and anti-inflammatory downstream signalling. Limiting the net efficacy of such compounds. In contrast, our recent landmark study, demonstrated that our prototype small-molecule agent, Compound 17b (Cmpd17b) is a biased FPR agonist, meaning it shows ligand-dependent selectivity for certain signal transduction pathways of FPRs. Cmpd17b directs signalling away from detrimental pro-inflammatory mechanisms and towards beneficial pro-survival pathways. We demonstrated that Cmpd17b reduces cardiac inflammation and remodelling, and preserves cardiac contractility after heart attack, but we have not investigated its effectiveness in other cardiopulmonary disorders, such as PH. Our exciting preliminary observations show that Cmpd17b dilates pulmonary arteries and reverses pulmonary fibrosis. Thus, targeting FPRs with Cmpd17b (and similar novel biased agonists) may improve vascular function and attenuate remodelling simultaneously, to improve clinical management of PH in terms of survival and quality of life.
The aim of this Honours project is to determine the therapeutic potential of novel FPR agonists to improve both vascular function and detrimental remodelling in PH. Biased FPR agonists may provide a superior therapeutic strategy for PH compared to conventional drugs. These novel FPR agonists might offer greater efficacy to target the underlying pathobiology of PH, as well as minimising negative side effects.
It is anticipated that this project will involve pre-clinical models of PH, isolated pulmonary vascular function with wire myography, in vitro profiling of biased FPR agonist signalling fingerprint in human pulmonary vascular cells and biochemical techniques including real-time qPCR, western blotting, immunohistochemistry and histology.