Since its discovery in 1926, human relaxin-2 (H2 relaxin) has undergone several clinical trials. It has finally passed the last Phase (Phase III) of the trials late last year for the treatment of acute heart failure. The indications are that H2 relaxin will enter into the clinic by the end of this year. However, this drug faces some limitations that need to be addressed in order to maximize its translational potential:
1. Cross-reactivity with other receptor: H2 relaxin exerts its biological function through its own receptor, Relaxin Family Peptide Receptor 1 (RXFP1; also known as LGR7). However, it also activates other receptors, including RXFP2 (native receptor for the related insulin-like peptide 3, INSL3). Thus, it would be beneficial to have a highly selective RXFP1 analogue to avoid potential undesired side effects mediated through RXFP2.
2. Large size and complex structure: The size (53 amino acids) and complex structure (two chains, A and B, and three disulfide bonds) of H2 relaxin represent a considerable challenge for its synthesis. This is a major limiting factor for the exploration of modifications of this peptide to optimize efficacy and stability. Thus a simpler H2 relaxin analogue that would be easier to prepare and modify is desirable.
Our recent structure-activity relationship (SAR) studies1,2,3 on H2 relaxin provide new insights into the mechanism of interaction of RXFP1 and RXFP2 by H2 relaxin, leading to a potent and RXFP1-selective minimized analogue.