Quick Project Snapshot
Novel single-chain peptide mimetics, 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 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 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.
Insulin Peptides Group
Insulin is one of the most clinically important peptide drugs on the market. It still represents the only treatment for diabetes (particularly for type 1). There are seven other insulin-like peptides (also called the relaxin family of peptides: H1, H2 and H3 relaxins, INSL3, 4, 5 and 6) which have similar structures to insulin (2 chains, 3 disulfide bonds), but have a diverse range of physiological functions. H2 relaxin is the most studied peptide in our laboratory and has recently passed phase III clinical trials for the treatment of acute heart failure. Our interest and experience lies in the design and development of insulin and insulin-like peptide-based drugs.
All Projects by this LabDeveloping peptidomimetics of insulin-like peptide 5, a novel orexigenic gut hormone, to target its GPCR, RXFP4Developing novel chemical methods to produce insulin mimeticsDeveloping small peptidomimetics to target RXFP1 for the treatment of acute heart failureNovel single-chain peptide mimetics, B7-33, for the treatment of fibrosisNovel relaxin-3 mimetics for controlling feeding and motivated behaviourNovel insulin-like peptide 5 mimetics for controlling colon motilityNovel insulin mimetics for managing diabetes
The Neuropeptides Division primarily conducts multi-disciplinary studies on the relaxin family of peptides/hormones and their receptors. The division focuses on determining the role of these peptides and the receptors they target a wide range of physiological and disease states. These studies are coupled with fundamental drug discovery research on both these and other peptides and their G protein-coupled receptors. The aim of this research is to develop new biological knowledge and fundamental understanding about how to best therapeutically target these peptide systems with the long term view to develop drugs which target the peptide receptors to treat vascular, fibrotic, metabolic and psychiatric diseases.
An example of the success of this approach is the completion of a Phase III trial using the hormone relaxin for the treatment of acute heart failure by the Swiss Pharmaceutical Company Novartis. A Phase IIIb trial is ongoing and the relaxin drug, serelaxin, has been approved in Russia to treat patients with acute heart failure. Hence fundamental research on the mechanism of action of a hormone, in the case of relaxin pioneered at the Florey by the former Neuropeptides Division Head, Prof Geoffrey Tregear, can ultimately lead to its use to treat disease in patients.