Unravelling fibrosis by pharmacological targeting of the G protein-coupled receptor, RXFP1

  • Hossain, Mohammed (Primary Chief Investigator (PCI))
  • Bathgate, Ross (Chief Investigator (CI))
  • Wade, John (Chief Investigator (CI))
  • Wade, John (Chief Investigator (CI))
  • Samuel, Chrishan (Chief Investigator (CI))
  • Yao, Song (Chief Investigator (CI))
  • Rosengren, Johan (Chief Investigator (CI))
  • Kocan, Martina (Chief Investigator (CI))

Project: Research

Project Description

Fibrosis and related disorders are among the leading causes of death worldwide highlighting the need for more direct and improved anti-fibrotic strategies.
While human relaxin-2 (H2) is now in Phase IIIb clinical trials for the treatment of acute heart failure (AHF), we have shown in animal models that H2 relaxin also 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 the 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 AHF. To achieve this goal, we will use our well established AlphaScreen cell signalling assays and also utilize state-of-the-art signalling sensors in fibroblasts and vascular cells (Aim 1). 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 (Aim 2). Finally B7-33 and stabilised analogs will be tested in clinically relevant experimental models of cardiac fibrosis to confirm their potential for translation as anti-fibrotic agents and/or AHF treatments (Aim 3).
Short titlePharmacological targeting of RXFP1
StatusActive
Effective start/end date1/01/1731/12/19

Funding

  • National Health & Medical Research Council (NHMRC): AUD798,618.00