Development of a synthetic relaxin-3/INSL5 chimeric peptide ligand for NanoBiT complementation binding assays

Wu, Hongkang; Hoare, Bradley L.; Handley, Thomas N.G.; Akhter Hossain, Mohammed; Bathgate, Ross A.D.

doi:10.1016/j.bcp.2024.116238

Biochemical Pharmacology

2024

DOI: 10.1016/j.bcp.2024.116238

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Development of a synthetic relaxin-3/INSL5 chimeric peptide ligand for NanoBiT complementation binding assays

Hongkang Wu,

Bradley L. Hoare,

Thomas N.G. Handley

et al.

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2024

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Cited by 2 publications

References 51 publications

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Developing insulin-like peptide 5-based antagonists for the G protein-coupled receptor, RXFP4

Wu,

Handley,

Hoare

et al. 2024

Biochemical Pharmacology

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Developing insulin-like peptide 5-based antagonists for the G protein-coupled receptor, RXFP4

Wu,

Handley,

Hoare

et al. 2024

Biochemical Pharmacology

View full text Add to dashboard Cite

Engineering of Novel Analogues That Are More Receptor-Selective and Potent than the Native Hormone, Insulin-like Peptide 5 (INSL5)

Wu,

Hartono,

Handley

et al. 2024

J. Med. Chem.

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Insulin-like peptide 5 (INSL5) targets the G protein-coupled receptor, relaxin family peptide receptor 4 (RXFP4), predominantly coexpressed in the colorectum. While INSL5 also binds to the related receptor RXFP3, it does not activate it. The INSL5/RXFP4 axis is a promising target for treating gastrointestinal disorders such as constipation. Despite its therapeutic potential, the clinical application of INSL5 has been hindered by synthesis complexities, necessitating the need for more accessible yet potent mimetics. In this study, we engineered an INSL5 analogue A13:B7-24-GG, featuring a simplified two-chain, two-disulfide scaffold with 32 amino acids, as opposed to the 45 amino acids found in native INSL5 (two-chain, three-disulfide), improving the synthesis yield by 19.5-fold. Additionally, A13:B7-24-GG demonstrates ∼4-fold higher potency (EC 50 = 1.17 nM vs 4.57 nM) and ∼11 times greater selectivity than native INSL5, with significantly reduced RXFP3 binding affinity, positioning it as a promising new therapeutic candidate for the treatment of constipation.

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Development of a synthetic relaxin-3/INSL5 chimeric peptide ligand for NanoBiT complementation binding assays

Cited by 2 publications

References 51 publications

Developing insulin-like peptide 5-based antagonists for the G protein-coupled receptor, RXFP4

Developing insulin-like peptide 5-based antagonists for the G protein-coupled receptor, RXFP4

Engineering of Novel Analogues That Are More Receptor-Selective and Potent than the Native Hormone, Insulin-like Peptide 5 (INSL5)

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