Angiotensin II (Ang II) is the main effector peptide hormone within the Renin-Angiotensin System (RAS) and is responsible for blood pressure regulation and cardiac remodelling. Ang II activates two main receptors, angiotensin type 1 (AT1R) and type 2 receptors (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 with great protective effects. Aberrant cardiac and renal remodelling stimulated after major Cardiovascular diseases (CVD) leads to fibrosis in the heart and kidney. Consequently, there is an urgent need for improved strategies for the treatment and prevention of fibrosis.

We have developed a peptide-based ligands library consisting of β-amino acid substitutions within the Angiotensin II/ III sequence which has resulted in significantly highly selective AT2R ligands as determined by radioligand binding assays of HEK permanently transfected cells with both receptors and in vitro plasma stability. Modifications to improve the selectivity and stability of these peptide have shown unprecedented selectivity profiles for AT2R and proven that, these ligands have function in vitro and in vivo.

Thus, the development of novel peptidomimetics is an attractive and potential tool in the field of drug design. Most significantly, this current work has resulted in several lead compounds with intensely high AT2R selectivity and stability and will now provide the opportunity to test highly selective AT2R agonists on cardiovascular function in chronic disease for potential drug development in the future.