Characterization of a new potent and long-lasting single chain peptide agonist of RXFP1 in cells and in vivo translational models.

Autor: Illiano S; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France. stephane.illiano@irsn.fr.; IRSN, B.P. 17, 92262, Fontenay-Aux-Roses Cedex, France. stephane.illiano@irsn.fr., Poirier B; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Minoletti C; Integrated Drug Discovery, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Pasquier O; DMPK France, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Riva L; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Chenede X; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Menguy I; Integrated Drug Discovery, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Guillotel M; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Prigent P; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Le Claire S; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Gillot F; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Thill G; Translational Science, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Lo Presti F; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Corbier A; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Le Bail JC; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Grailhe P; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Monteagudo E; Peptides and Small Molecules R&D Department, ≠DMPK, and Structural Biology IRBM Spa, Via Pontina Km 30 600, 00 071, Pomezia, RM, Italy., Ingenito R; Peptides and Small Molecules R&D Department, ≠DMPK, and Structural Biology IRBM Spa, Via Pontina Km 30 600, 00 071, Pomezia, RM, Italy., Bianchi E; Peptides and Small Molecules R&D Department, ≠DMPK, and Structural Biology IRBM Spa, Via Pontina Km 30 600, 00 071, Pomezia, RM, Italy., Philippo C; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Duclos O; Integrated Drug Discovery, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France., Mallart S; Integrated Drug Discovery, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France.; Structural biology and chemistry, Institut Pasteur, PARIS, France., Bathgate R; Florey Institute of Neuroscience and Mental Health and Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC, 3052, Australia., Janiak P; Cardio-Vascular and Metabolism, Sanofi R&D, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Nov 28; Vol. 12 (1), pp. 20435. Date of Electronic Publication: 2022 Nov 28.
DOI: 10.1038/s41598-022-24716-2
Abstrakt: Despite beneficial effects in acute heart failure, the full therapeutic potential of recombinant relaxin-2 has been hampered by its short half-life and the need for intravenous administration limiting its use to intensive care units. A multiparametric optimization of the relaxin B-chain led to the identification of single chain lipidated peptide agonists of RXFP1 like SA10SC-RLX with subcutaneous bioavailability and extended half-life. SA10SC-RLX has sub nanomolar activity on cells expressing human RXFP1 and molecular modeling associated with the study of different RXFP1 mutants was used to decipher the mechanism of SA10SC-RLX interaction with RXFP1. Telemetry was performed in rat where SA10SC-RLX was able to engage RXFP1 after subcutaneous administration without tachyphylaxis after repeated dosing. Renal blood flow was then used as a translational model to evaluate RXFP1 activation. SA10SC-RLX increased renal blood flow and decreased renal vascular resistance in rats as reported for relaxin in humans. In conclusion, SA10SC-RLX mimics relaxin activity in in vitro and in vivo models of acute RXFP1 engagement. SA10SC-RLX represents a new class of long-lasting RXFP1 agonist, suitable for once daily subcutaneous administration in patients and potentially paving the way to new treatments for chronic fibrotic and cardiovascular diseases.
(© 2022. The Author(s).)
Databáze: MEDLINE
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