TY - JOUR
T1 - Further Developments towards a Minimal Potent Derivative of Human Relaxin-2
AU - Handley, Thomas N.G.
AU - Praveen, Praveen
AU - Tailhades, Julien
AU - Wu, Hongkang
AU - Bathgate, Ross A.D.
AU - Hossain, Mohammed Akhter
N1 - Funding Information:
This work was supported by the National Health & Medical Research Council (NHMRC) of Australia Grants to M.A. Hossain (GNT2001178), R.A.D. Bathgate (GNT2001027), and an NHMRC Senior Research Fellowship to R.A.D. Bathgate (GNT1135837). Studies at the Florey were supported by the Victorian Government’s Operational Infrastructure Support Program.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/8
Y1 - 2023/8
N2 - Human relaxin-2 (H2 relaxin) is a peptide hormone with potent vasodilatory and anti-fibrotic effects, which is of interest for the treatment of heart failure and fibrosis. H2 relaxin binds to the Relaxin Family Peptide Receptor 1 (RXFP1). Native H2 relaxin is a two-chain, three-disulfide-bond-containing peptide, which is unstable in human serum and difficult to synthesize efficiently. In 2016, our group developed B7-33, a single-chain peptide derived from the B-chain of H2 relaxin. B7-33 demonstrated poor affinity and potency in HEK cells overexpressing RXFP1; however, it displayed equivalent potency to H2 relaxin in fibroblasts natively expressing RXFP1, where it also demonstrated the anti-fibrotic effects of the native hormone. B7-33 reversed organ fibrosis in numerous pre-clinical animal studies. Here, we detail our efforts towards a minimal H2 relaxin scaffold and attempts to improve scaffold activity through Aib substitution and hydrocarbon stapling to re-create the peptide helicity present in the native H2 relaxin.
AB - Human relaxin-2 (H2 relaxin) is a peptide hormone with potent vasodilatory and anti-fibrotic effects, which is of interest for the treatment of heart failure and fibrosis. H2 relaxin binds to the Relaxin Family Peptide Receptor 1 (RXFP1). Native H2 relaxin is a two-chain, three-disulfide-bond-containing peptide, which is unstable in human serum and difficult to synthesize efficiently. In 2016, our group developed B7-33, a single-chain peptide derived from the B-chain of H2 relaxin. B7-33 demonstrated poor affinity and potency in HEK cells overexpressing RXFP1; however, it displayed equivalent potency to H2 relaxin in fibroblasts natively expressing RXFP1, where it also demonstrated the anti-fibrotic effects of the native hormone. B7-33 reversed organ fibrosis in numerous pre-clinical animal studies. Here, we detail our efforts towards a minimal H2 relaxin scaffold and attempts to improve scaffold activity through Aib substitution and hydrocarbon stapling to re-create the peptide helicity present in the native H2 relaxin.
KW - 7BP
KW - B7-33
KW - B9-31
KW - fibrosis
KW - human relaxin-2
KW - peptide synthesis
KW - RXFP1
UR - http://www.scopus.com/inward/record.url?scp=85168726359&partnerID=8YFLogxK
U2 - 10.3390/ijms241612670
DO - 10.3390/ijms241612670
M3 - Article
C2 - 37628851
AN - SCOPUS:85168726359
SN - 1661-6596
VL - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 16
M1 - 12670
ER -