Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin-2 for Cardiovascular Diseases
Sergio Mallart, Raffaele Ingenito, Elisabetta Bianchi, Alberto Bresciani, Simone Esposito, Mariana Gallo, Paola Magotti, Edith Monteagudo, Laura Orsatti, Daniela Roversi, Alessia Santoprete, Federica Tucci, Maria Veneziano, Régine Bartsch, Claudius Boehm, Denis Brasseur, Patricia Bruneau, Alain Corbier, Jacques Froissant, Laurence Gauzy‐Lazo, Vincent Gervat, Frank Marguet, Isabelle Menguy, Claire Minoletti, Marie-Françoise Nicolas, Olivier Pasquier, Bruno Poirier, Alexandre Raux, Laurence Riva, Philip Janiak, Hartmut Strobel, Olivier Duclos, Stéphane Illiano
Abstract
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).