Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds
Relaxin-3 is a neuropeptide with important roles in metabolism, arousal, learning and memory. Its cognate receptor is the relaxin family peptide-3 (RXFP3) receptor. Relaxin-3 agonist and antagonist analogs have been shown to be able to modulate food intake in rodent models. The relaxin-3 B-chain is...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-02-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2020.00087/full |
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| author | Han Siean Lee Michael Postan Angela Song Richard J. Clark Ross A. D. Bathgate Ross A. D. Bathgate Linda M. Haugaard-Kedström K. Johan Rosengren |
| author_facet | Han Siean Lee Michael Postan Angela Song Richard J. Clark Ross A. D. Bathgate Ross A. D. Bathgate Linda M. Haugaard-Kedström K. Johan Rosengren |
| author_sort | Han Siean Lee |
| collection | DOAJ |
| description | Relaxin-3 is a neuropeptide with important roles in metabolism, arousal, learning and memory. Its cognate receptor is the relaxin family peptide-3 (RXFP3) receptor. Relaxin-3 agonist and antagonist analogs have been shown to be able to modulate food intake in rodent models. The relaxin-3 B-chain is sufficient for receptor interactions, however, in the absence of a structural support, linear relaxin-3 B-chain analogs are rapidly degraded and thus unsuitable as drug leads. In this study, two different disulfide-stabilized scaffolds were used for grafting of important relaxin-3 B-chain residues to improve structure and stability. The use of both Veronica hederifolia Trypsin inhibitor (VhTI) and apamin grafting resulted in agonist and antagonist analogs with improved helicity. VhTI grafted peptides showed poor binding and low potency at RXFP3, on the other hand, apamin variants retained significant activity. These variants also showed improved half-life in serum from ~5 min to >6 h, and thus are promising RXFP3 specific pharmacological tools and drug leads for neuropharmacological diseases. |
| first_indexed | 2024-12-19T20:39:15Z |
| format | Article |
| id | doaj.art-c183aee3f6d549afbc6228b8eaf12157 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-19T20:39:15Z |
| publishDate | 2020-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-c183aee3f6d549afbc6228b8eaf121572022-12-21T20:06:27ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462020-02-01810.3389/fchem.2020.00087495592Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized ScaffoldsHan Siean Lee0Michael Postan1Angela Song2Richard J. Clark3Ross A. D. Bathgate4Ross A. D. Bathgate5Linda M. Haugaard-Kedström6K. Johan Rosengren7Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, AustraliaFaculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, AustraliaFaculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, AustraliaFaculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, AustraliaFlorey Department of Neuroscience and Mental Health, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, AustraliaDepartment of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, VIC, AustraliaFaculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, AustraliaFaculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, AustraliaRelaxin-3 is a neuropeptide with important roles in metabolism, arousal, learning and memory. Its cognate receptor is the relaxin family peptide-3 (RXFP3) receptor. Relaxin-3 agonist and antagonist analogs have been shown to be able to modulate food intake in rodent models. The relaxin-3 B-chain is sufficient for receptor interactions, however, in the absence of a structural support, linear relaxin-3 B-chain analogs are rapidly degraded and thus unsuitable as drug leads. In this study, two different disulfide-stabilized scaffolds were used for grafting of important relaxin-3 B-chain residues to improve structure and stability. The use of both Veronica hederifolia Trypsin inhibitor (VhTI) and apamin grafting resulted in agonist and antagonist analogs with improved helicity. VhTI grafted peptides showed poor binding and low potency at RXFP3, on the other hand, apamin variants retained significant activity. These variants also showed improved half-life in serum from ~5 min to >6 h, and thus are promising RXFP3 specific pharmacological tools and drug leads for neuropharmacological diseases.https://www.frontiersin.org/article/10.3389/fchem.2020.00087/fullrelaxin-3RXFP3graftingapaminVhTIdisulfide-scaffold |
| spellingShingle | Han Siean Lee Michael Postan Angela Song Richard J. Clark Ross A. D. Bathgate Ross A. D. Bathgate Linda M. Haugaard-Kedström K. Johan Rosengren Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds Frontiers in Chemistry relaxin-3 RXFP3 grafting apamin VhTI disulfide-scaffold |
| title | Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds |
| title_full | Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds |
| title_fullStr | Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds |
| title_full_unstemmed | Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds |
| title_short | Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds |
| title_sort | development of relaxin 3 agonists and antagonists based on grafted disulfide stabilized scaffolds |
| topic | relaxin-3 RXFP3 grafting apamin VhTI disulfide-scaffold |
| url | https://www.frontiersin.org/article/10.3389/fchem.2020.00087/full |
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