Novel single-chain peptide mimetics of relaxin-2, B7-33, for the treatment of fibrosis

Fibrosis and related disorders are among the leading causes of death worldwide highlighting the need for more direct and improved anti-fibrotic strategies.

We have shown in animal models that H2 relaxin has therapeutic potential for fibrosis and related disorders. However, the H2 peptide has a complex insulin-like 2 chain structure with three disulphide bonds and short plasma half-life that makes the peptide expensive to manufacture and less effective as a long-term drug treatment. In a major breakthrough published in Chemical Science (flagship journal, Royal Society of Chemistry) we discovered a single-chain variant of H2 relaxin (B7-33) which has no disulfide bridges, and which is easy to manufacture and modify to improve its in vivo plasma half-life.

B7-33 was shown to specifically bind the relaxin receptor, RXFP1, and preferentially activate pathways related to anti-fibrotic effects in fibroblast in vitro and in rats and mouse models of fibrosis in vivo without side effects. Thus, B7-33 represents the first single-chain functionally-selective agonist of RXFP1. In this proposed study, we will unravel the pharmacological basis of functional selectivity of B7-33.

Additionally we will test if B7-33 is able to mimic other actions of H2 relaxin related to heart failure. We will further modify and optimise our current lead B7-33 by using rational structure-based drug design and medicinal chemistry techniques (stapling, lipidation etc) to improve in vivo half-life. Finally B7-33 and stabilised analogs will be tested in clinically relevant experimental models of cardiac fibrosis to confirm their potential for translation as an anti-fibrotic agent.