TY - JOUR
T1 - A Lipidated Single-B-Chain Derivative of Relaxin Exhibits Improved In Vitro Serum Stability without Altering Activity
AU - Praveen, Praveen
AU - Wang, Chao
AU - Handley, Thomas N.G.
AU - Wu, Hongkang
AU - Samuel, Chrishan S.
AU - Bathgate, Ross A.D.
AU - Hossain, Mohammed Akhter
N1 - Funding Information:
This work was supported by National Health & Medical Research Council (NHMRC) of Australia Grants to M.A. Hossain and C.S. Samuel (GNT2001178); and R.A.D. Bathgate (GNT2001027); an NHMRC Senior Research Fellowship to R.A.D. Bathgate (GNT1135837); and a Monash Biomedicine Discovery Institute Senior Research Fellowship to C.S. Samuel. Studies at the Florey Institute were supported by the Victorian Government’s Operational Infrastructure Support Program.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
KW - B7-33
KW - H2 relaxin
KW - RXFP1
KW - structure-activity relationship (SAR)
UR - https://www.scopus.com/pages/publications/85152334040
U2 - 10.3390/ijms24076616
DO - 10.3390/ijms24076616
M3 - Article
C2 - 37047588
AN - SCOPUS:85152334040
SN - 1422-0067
VL - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 7
M1 - 6616
ER -