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The challenges of targeting RXFP1, the receptor for the heart failure drug candidate relaxin, with peptide mimetics and small molecules
- Dr. Ross Bathgate -
- Florey Institute of Neuroscience and Mental Health -
- Parkville, Australia -
Abstract
The peptide hormone relaxin activates the GPCR relaxin family peptide 1 (RXFP1) receptor. Relaxin has demonstrated considerable promise as a treatment for cardiovascular disease and fibrosis. While it did not meet primary endpoints in a Phase IIIb study in acute heart failure, patients showed improvements in markers of cardiac, renal, and hepatic damage consistent with the prevention of organ damage. Relaxin is an insulin-like two-chain disulphide linked peptide which is not orally active and has a short in vivo half-life necessitating intravenous infusion. Hence the development of peptide mimetics or small molecule agonists is advantageous, especially for chronic treatment. Consequently, modified relaxin analogs and small molecules targeting RXFP1 are undergoing development by numerous pharmaceutical companies.
Our group has demonstrated that relaxin-mediated RXFP1 activation involves multiple ligand-receptor interactions and conformational changes resulting in the linker region between the N-terminal LDLa module and LRR domain activating the receptor as a tethered ligand. This complex activation mode makes the development of agonists that exactly mimic the mode of relaxin activation challenging. In line with this, we have previously shown that the small molecule RXFP1 agonist ML290 is a biased agonist. More recently, we developed a single chain relaxin mimetic peptide, B7-33, and demonstrated that low-affinity B7-33 binding strongly activates Gi-mediated signaling pathways while poorly activating Gs signaling and cAMP activation. This presentation will discuss the mechanism of biased signaling by relaxin peptidomimetics and the challenges of mimetic design for complex peptide GPCR targets like RXFP1.
Author list and affiliations
Ross AD Bathgate1,2, Daniel Scott1,2, Chris Draper-Joyce1, Paul R Gooley2, Mohammed Akhter Hossain1,3 1Florey Institute of Neuroscience & Mental Health, 2Department of Biochemistry & Pharmacology, 3School of Chemistry, the University of Melbourne, Parkville, Victoria, Australia 3010.
About Dr. Ross Bathgate
Professor Ross Bathgate is the leader of the Neurotherapeutics theme at the Florey Institute of Neuroscience and Mental Health and is an Honorary Professorial Fellow in the Department of Biochemistry and Pharmacology at the University of Melbourne, Australia. His lab focuses on understanding the interactions of peptide ligands with their G protein-coupled receptor (GPCR) targets for the development of peptide-based drugs and utilizing structure-based drug design to develop novel therapeutics. He has authored over 270 publications including many reviews on the relaxin family of peptides and their GPCRs. Peptides of the relaxin family show enormous therapeutic potential particularly the peptide hormone relaxin which has been utilized in Phase III clinical trials for the treatment of acute heart failure. He works closely with a number of pharmaceutical companies interested in the clinical development of relaxin mimetics as well as other companies interested in peptide GPCR targets.
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