抄録
In humans, the peptide apelin activates a single GPCR to cause potent cardiac inotropic effects as well as peripheral vasodilatation (1,2). The peptide is down regulated in pulmonary arterial hypertension (PAH) suggesting synthetic agonists would be of therapeutic benefit. A limitation of many agonists acting at GPCRs is that, after signalling via G-proteins to produce a physiological action, the target receptor is internalised via the beta-arrestin pathway.
Using computational chemistry, we have designed and identified a 'biased' cyclic peptide apelin agonist, MM07 and shown that it has comparable activity to the native peptide in G-protein mediated pathways in vitro but lower beta-arrestin and internalization activity. MM07 caused rapid peripheral arterial dilatation human forearm. Importantly, there was no evidence of desensitization when repeated infusions were given suggesting that MMO7 would be more efficacious than apelin (3). MM07 also significantly attenuated the development of PAH in a rat model. Mutations in the apelin receptor have been identified from the100,000 Genomes Project BRIDGE in patients with rare diseases including PAH, where apelin binding was reduced or abolished. We have also demonstrated that G-protein bias can be retained in a non-peptide analogue, CMF019. In vivo, this compound caused a significant increase in cardiac contractility and provides the basis for design of biased agonists with improved pharmacokinetics.
We have recently discovered that a novel peptide Elabela or Toddler originally identified in fish, Danio that is critical for heart development, is a second ligand for the human apelin receptor (4). Comparable to apelin, Elabela increased cardiac contractility, ejection fraction, and cardiac output and elicited vasodilatation in rat in vivo. Ela expression was reduced in cardiopulmonary tissues from PAH patients and Ela treatment significantly attenuated elevation of right ventricular systolic pressure and right ventricular hypertrophy and pulmonary vascular remodeling in monocrotaline-exposed rats. These results suggest both peptides are downregulated in PAH suggesting the apelin receptor as a new target in the treatment of this condition using biased agonists.
1.Maguire et al. (2009),Hypertension,54:598-604 2. Yang et al.,(2015),Trends Pharmacol Sci. 36:560-567 3.Brame et al.,(2015),Hypertension 65: 834-40. 4. Read et al.(2016) Biochem Pharmacol.116:63-72. 4.Yang et al.,2017,Circulation,135:1160-1173.
