R2R01: A long-acting single-chain peptide agonist of RXFP1 for renal and cardiovascular diseases.

Autor: Poirier B; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France., Pasquier O; Integrated Drug Discovery, Sanofi R&D, Chilly Mazarin, France., Chenede X; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France., Corbier A; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France., Prigent P; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France., Azam A; DMPK France, Sanofi R&D, Chilly Mazarin, France., Bernard C; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France., Guillotel M; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France., Gillot F; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France., Riva L; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France., Briand V; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France., Ingenito R; Peptides and Small Molecules R&D Department, IRBM Spa, Pomezia, Rome, Italy., Gauzy-Lazo L; Département Médicaments et Technologies pour la Santé, Université de Paris-Saclay, CEA, INRAE, Gif-sur-Yvette, France., Duclos O; Département Médicaments et Technologies pour la Santé, Université de Paris-Saclay, CEA, INRAE, Gif-sur-Yvette, France., Philippo C; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France., Maillere B; DMPK France, Sanofi R&D, Chilly Mazarin, France., Bianchi E; Peptides and Small Molecules R&D Department, IRBM Spa, Pomezia, Rome, Italy., Mallart S; Département Médicaments et Technologies pour la Santé, Université de Paris-Saclay, CEA, INRAE, Gif-sur-Yvette, France., Janiak P; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France., Illiano S; Cardio-Vascular and metabolism, Sanofi R&D, Chilly Mazarin, France.; Investigative Toxicology, Sanofi R&D, Chilly Mazarin, France.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Jul; Vol. 181 (13), pp. 1993-2011. Date of Electronic Publication: 2024 Mar 07.
DOI: 10.1111/bph.16338
Abstrakt: Background: The therapeutic potential of relaxin for heart failure and renal disease in clinical trials is hampered by the short half-life of serelaxin. Optimization of fatty acid-acetylated single-chain peptide analogues of relaxin culminated in the design and synthesis of R2R01, a potent and selective RXFP1 agonist with subcutaneous bioavailability and extended half-life.
Experimental Approach: Cellular assays and pharmacological models of RXFP1 activation were used to validate the potency and selectivity of R2R01. Increased renal blood flow was used as a translational marker of R2R01 activity. Human mastocytes (LAD2 cells) were used to study potential pseudo-allergic reactions and CD4+ T-cells to study immunogenicity. The pharmacokinetics of R2R01 were characterized in rats and minipigs.
Key Results: In vitro, R2R01 had comparable potency and efficacy to relaxin as an agonist for human RXFP1. In vivo, subcutaneous administration of R2R01 increased heart rate and renal blood flow in normotensive and hypertensive rat and did not show evidence of tachyphylaxis. R2R01 also increased nipple length in rats, used as a chronic model of RXFP1 engagement. Pharmacokinetic studies showed that R2R01 has a significantly extended terminal half-life. The in vitro assays with LAD2 cells and CD4+ T-cells showed that R2R01 had low potential for pseudo-allergic and immunogenic reactions, respectively.
Conclusion and Implications: R2R01 is a potent RXFP1 agonist with an extended half-life that increases renal blood flow in various settings including normotensive and hypertensive conditions. The preclinical efficacy and safety data supported clinical development of R2R01 as a potential new therapy for renal and cardiovascular diseases.
(© 2024 British Pharmacological Society.)
Databáze: MEDLINE
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