The minimal active structure of human relaxin-2

Area of Science:

• Biochemistry
• Endocrinology
• Pharmacology

Background:

• Human relaxin 2 (H2 relaxin) is a peptide hormone with therapeutic potential for acute heart failure.
• Its complex structure poses challenges for chemical synthesis and modification.
• H2 relaxin regulates collagen metabolism and vascular pathways, influencing vasodilation and renal function.

Purpose of the Study:

• To overcome synthetic challenges by creating and evaluating H2 relaxin analogues with truncated termini.
• To identify critical regions of H2 relaxin responsible for receptor interaction and biological activity.
• To develop a receptor-selective H2 relaxin analogue for therapeutic development.

Main Methods:

• Solid phase peptide synthesis of 24 H2 relaxin analogues with N- and C-terminal truncations.
• Structural and functional evaluation of synthesized analogues.
• Assessment of receptor selectivity (RXFP1 vs. RXFP2) and biological activity, including antifibrotic effects in human BJ3 cells.

Main Results:

• Significant truncation of the B-chain termini retained potent biological activity, indicating these regions are not critical for RXFP1 interaction.
• Truncations reduced activity at RXFP2, enhancing selectivity for RXFP1.
• A minimized 38-amino acid active core demonstrated comparable antifibrotic activity to native H2 relaxin.

Conclusions:

• The study identified a critical active core of H2 relaxin, essential for its biological functions.
• Truncated analogues exhibit improved selectivity for the RXFP1 receptor.
• The minimized core represents a promising lead for developing novel, receptor-selective relaxin-based therapeutics.