Characterization of a new potent and long-lasting single chain peptide agonist of RXFP1 in cells and in vivo translational models.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
28 11 2022
28 11 2022
Historique:
received:
12
07
2022
accepted:
18
11
2022
entrez:
28
11
2022
pubmed:
29
11
2022
medline:
1
12
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36443381
doi: 10.1038/s41598-022-24716-2
pii: 10.1038/s41598-022-24716-2
pmc: PMC9705314
doi:
Substances chimiques
Relaxin
9002-69-1
RXFP1 protein, human
0
Receptors, Peptide
0
Receptors, G-Protein-Coupled
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
20435Subventions
Organisme : National Health and Medical Research Council of Australia Research Fellowship
ID : 1135837
Informations de copyright
© 2022. The Author(s).
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