Exploiting Biased Agonists of Formyl Peptide Receptors as Pharmacotherapy for Pulmonary Hypertension: simultaneous targeting of vascular function and remodelling

Pulmonary hypertension is a rare but commonly fatal cardiopulmonary disease with a survival rate commonly less than 5 years. There is a clear
clinical need for developing an innovative treatment for this disease. The applicants have identified a small molecule formyl peptide receptor
(FPR) agonist (Cmpd17b) which exerts biased signalling away from detrimental pro-inflammatory mechanisms to provide superior protection
against myocardial injury. Recent evidence from the applicants’ laboratory indicates that Cmpd17b not only dilates pulmonary arteries, but also
limits vascular remodelling, suggesting that Cmpd17b may be an attractive therapy against pulmonary hypertension. We will integrate our
comprehensive drug evaluation system with conventional and innovative methodologies to evaluate biased FPR agonists as a novel treatment for
pulmonary hypertension. We will assess functional responses (vasodilator response-Aim 1A) and vascular remodelling-Aim 2A) in pulmonary
arteries, and establish the signalling fingerprint of FPR agonists with various actions (balanced, biased) under disease conditions in human
pulmonary cells in vitro (Aims 1B, 2B). We will then evaluate drug efficacy in pre-clinical models of pulmonary hypertension in vivo (Aim 3).
We anticipate that biased FPR pharmacotherapy will improve vascular remodelling and reduce vasoconstriction associated with pulmonary
hypertension, ultimately improving cardiovascular function in vivo. Our research may lead to innovative and vital pharmacotherapies to treat
pulmonary hypertension.