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

• Published in: International journal of molecular sciences 2023-04, Vol.24 (7), p.6616
• Main Authors: Praveen, Praveen, Wang, Chao, Handley, Thomas N G, Wu, Hongkang, Samuel, Chrishan S, Bathgate, Ross A D, Hossain, Mohammed Akhter
• Format: Article
• Language: English
• Subjects: Amino acids; Animal models; Animals; B7-33; Carbon; Chains; Communication; Congestive heart failure; Conjugation; Exhibitions; Fatty acids; Fibroblasts; Fibrosis; H2 relaxin; Humans; Liraglutide; Peptides; Proteins; Receptors, G-Protein-Coupled - chemistry; Relaxin; Relaxin - pharmacology; RXFP1; Structure-Activity Relationship; structure-activity relationship (SAR)
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24076616

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 (t = ~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.