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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039932/ https://www.ncbi.nlm.nih.gov/pubmed/32133341 http://dx.doi.org/10.3389/fchem.2020.00087 |
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author | Lee, Han Siean Postan, Michael Song, Angela Clark, Richard J. Bathgate, Ross A. D. Haugaard-Kedström, Linda M. Rosengren, K. Johan |
author_facet | Lee, Han Siean Postan, Michael Song, Angela Clark, Richard J. Bathgate, Ross A. D. Haugaard-Kedström, Linda M. Rosengren, K. Johan |
author_sort | Lee, Han Siean |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-7039932 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70399322020-03-04 Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds Lee, Han Siean Postan, Michael Song, Angela Clark, Richard J. Bathgate, Ross A. D. Haugaard-Kedström, Linda M. Rosengren, K. Johan Front Chem Chemistry 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. Frontiers Media S.A. 2020-02-18 /pmc/articles/PMC7039932/ /pubmed/32133341 http://dx.doi.org/10.3389/fchem.2020.00087 Text en Copyright © 2020 Lee, Postan, Song, Clark, Bathgate, Haugaard-Kedström and Rosengren. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Chemistry Lee, Han Siean Postan, Michael Song, Angela Clark, Richard J. Bathgate, Ross A. D. Haugaard-Kedström, Linda M. Rosengren, K. Johan Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds |
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 | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039932/ https://www.ncbi.nlm.nih.gov/pubmed/32133341 http://dx.doi.org/10.3389/fchem.2020.00087 |
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