Angiotensin II is the main effector peptide hormone within the renin angiotensin system (RAS) and is responsible for blood pressure regulation and cardiac remodelling. Angiotensin II activates two main receptors (AT1R and AT2R) within the RAS, which have opposing functions. Activation of AT1R promotes growth and proliferation, cardiovascular remodelling and vasoconstriction whilst AT2R activation inhibits remodelling and inflammation and mediates NO-dependent vasodilation. However, there are only a few selective agonists for the AT2R.
We have designed and synthesised a peptide library consisting of β-amino acid substitutions within the Angiotensin II sequence which has resulted in highly selective AT2R ligands as seen by radioligand binding assays and ex vivo preparations [1, 2]. We have used these compounds as templates to introduce further modifications to improve the selectivity and stability of these peptide ligands. We have developed stable peptide-based ligands that show unprecedented selectivity profiles for AT2R and show these ligands to have function in vitro and in vivo. Thus, the current approach to design and synthesise novel AT2R-selective peptidomimetics will inform on AT2R function and shows great potential in the development of future AT2R-selective therapeutics for cardiovascular disease.