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

摘要: 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 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential been hampered by short half-life and need for intravenous administration limiting use to intensive care units. In this study, we report development of long-acting potent single-chain relaxin mimetics. Modifications B-chain relaxin, such introduction specific mutations trimming sequence an optimal size, resulted potent, structurally simplified agonists receptor Relaxin Family Peptide Receptor 1 (RXFP1) (e.g., 54). Introduction suitable spacers fatty acids led identification lipidated RXFP1, with sub-nanomolar activity, high subcutaneous bioavailability, extended half-lives, vivo efficacy 64).