A Lipidated Single-B-Chain Derivative of Relaxin Exhibits Improved In Vitro Serum Stability without Altering Activity.

Abstract

Human relaxin-2 (H2 relaxin) is therapeutically very important due to its strong anti-fibrotic, vasodilatory, and cardioprotective effects. Therefore, relaxin's receptor, relaxin family peptide receptor 1 (RXFP1), is a potential target for the treatment of fibrosis and related disorders, including heart failure. H2 relaxin has a complex two-chain structure (A and B) and three disulfide bridges. Our laboratory has recently developed B7-33 peptide, a single-chain agonist based on the B-chain of H2 relaxin. However, the peptide B7-33 has a short circulation time in vitro in serum (t1/2 = ~6 min). In this study, we report structure-activity relationship studies on B7-33 utilizing different fatty-acid conjugations at different positions. We have shown that by fatty-acid conjugation with an appropriate spacer length, the in vitro half-life of B7-33 can be increased from 6 min to 60 min. In the future, the lead lipidated molecule will be studied in animal models to measure its PK/PD properties, which will lead to their pre-clinical applications.

• Authors: Praveen Praveen, Chao Wang, Thomas N G Handley, Hongkang Wu, Chrishan S Samuel, Ross A D Bathgate, Mohammed Akhter Hossain
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 7 (Apr 01 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37047588 (Publication Type: Journal Article)

Chemical References

• Relaxin
• Receptors, G-Protein-Coupled

Topics

• Animals
• Humans
• Relaxin (pharmacology)
• Receptors, G-Protein-Coupled (chemistry)
• Structure-Activity Relationship
• Fibrosis