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

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).