1. Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin-2 for Cardiovascular Diseases
- Author
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Paola Magotti, Laura Orsatti, Sergio Mallart, Edith Monteagudo, Isabelle Menguy, Bruno Poirier, Olivier Pasquier, Elisabetta Bianchi, Hartmut Strobel, Claudius Boehm, Raffaele Ingenito, Olivier Duclos, Laurence Gauzy-Lazo, Philip Janiak, Simone Esposito, Patricia Bruneau, Federica Tucci, Maria Veneziano, Claire Minoletti, Alessia Santoprete, Alexandre Raux, Daniela Roversi, Laurence Riva, Denis Brasseur, Regine Bartsch, Alberto Bresciani, Jacques Froissant, Marie-Françoise Nicolas, Mariana Gallo, Frank Marguet, Vincent Gervat, Stéphane Illiano, and Alain Corbier
- Subjects
Male ,Receptors, Peptide ,Peptide ,Molecular Dynamics Simulation ,Pharmacology ,01 natural sciences ,Receptors, G-Protein-Coupled ,Rats, Sprague-Dawley ,Lipopeptides ,Structure-Activity Relationship ,03 medical and health sciences ,Serelaxin ,In vivo ,Cell Line, Tumor ,Intensive care ,Drug Discovery ,Animals ,Humans ,Amino Acid Sequence ,Receptor ,Peptide sequence ,030304 developmental biology ,chemistry.chemical_classification ,Relaxin ,0303 health sciences ,Molecular Structure ,urogenital system ,Chemistry ,0104 chemical sciences ,Protein Subunits ,010404 medicinal & biomolecular chemistry ,HEK293 Cells ,Cardiovascular Diseases ,Mutation ,Molecular Medicine ,hormones, hormone substitutes, and hormone antagonists ,Half-Life ,Relaxin receptor - 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).
- Published
- 2021