Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin-2 for Cardiovascular Diseases

J Med Chem. 2021 Feb 25;64(4):2139-2150. doi: 10.1021/acs.jmedchem.0c01533. Epub 2021 Feb 8.


The insulin-like peptide human relaxin-2 was identified as a hormone that, among other biological functions, mediates the hemodynamic changes occurring during pregnancy. Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been hampered by its short half-life and the need for intravenous administration limiting its use to intensive care units. In this study, we report the development of long-acting potent single-chain relaxin peptide mimetics. Modifications in the B-chain of relaxin, such as the introduction of specific mutations and the trimming of the sequence to an optimal size, resulted in potent, structurally simplified peptide agonists of the relaxin receptor Relaxin Family Peptide Receptor 1 (RXFP1) (e.g., 54). Introduction of suitable spacers and fatty acids led to the identification of single-chain lipidated peptide agonists of RXFP1, with sub-nanomolar activity, high subcutaneous bioavailability, extended half-lives, and in vivo efficacy (e.g., 64).

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cardiovascular Diseases
  • Cell Line, Tumor
  • HEK293 Cells
  • Half-Life
  • Humans
  • Lipopeptides / genetics
  • Lipopeptides / pharmacokinetics
  • Lipopeptides / pharmacology*
  • Male
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Mutation
  • Protein Subunits
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, Peptide / agonists*
  • Relaxin / analogs & derivatives*
  • Relaxin / genetics
  • Relaxin / pharmacology*
  • Structure-Activity Relationship


  • Lipopeptides
  • Protein Subunits
  • RLN2 protein, human
  • RXFP1 protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • Relaxin