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Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides
We describe two synthetic amino acids with inverted side chain stereochemistry, which induce opposite biological activity. Phe(4) is an important part of the activation motif of ghrelin, and in short peptide inverse agonists such as KwFwLL‐NH(2), the aromatic core is necessary for inactivation of th...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899459/ https://www.ncbi.nlm.nih.gov/pubmed/31442005 http://dx.doi.org/10.1002/cmdc.201900409 |
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author | Nicke, Lennart Müller, Ronny Geyer, Armin Els‐Heindl, Sylvia |
author_facet | Nicke, Lennart Müller, Ronny Geyer, Armin Els‐Heindl, Sylvia |
author_sort | Nicke, Lennart |
collection | PubMed |
description | We describe two synthetic amino acids with inverted side chain stereochemistry, which induce opposite biological activity. Phe(4) is an important part of the activation motif of ghrelin, and in short peptide inverse agonists such as KwFwLL‐NH(2), the aromatic core is necessary for inactivation of the receptor. To restrict indole/phenyl mobility and simultaneously strengthen the interaction between peptide and receptor, we exchanged the natural monoaryl amino acids for diaryl amino acids derived from tryptophan. By standard solid‐phase peptide synthesis, each of them was inserted into ghrelin or in the aromatic core of the inverse agonist. Both ghrelin analogues showed nanomolar activity, indicating sufficient space to accommodate the additional side chain. In contrast, diaryl amino acids in the inverse agonist had considerable influence on receptor signaling. Whereas the introduction of Wsf maintains inverse agonism of the peptide, Wrf shifts the receptor more to active states and can induce agonism depending on its introduction site. |
format | Online Article Text |
id | pubmed-6899459 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-68994592019-12-19 Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides Nicke, Lennart Müller, Ronny Geyer, Armin Els‐Heindl, Sylvia ChemMedChem Full Papers We describe two synthetic amino acids with inverted side chain stereochemistry, which induce opposite biological activity. Phe(4) is an important part of the activation motif of ghrelin, and in short peptide inverse agonists such as KwFwLL‐NH(2), the aromatic core is necessary for inactivation of the receptor. To restrict indole/phenyl mobility and simultaneously strengthen the interaction between peptide and receptor, we exchanged the natural monoaryl amino acids for diaryl amino acids derived from tryptophan. By standard solid‐phase peptide synthesis, each of them was inserted into ghrelin or in the aromatic core of the inverse agonist. Both ghrelin analogues showed nanomolar activity, indicating sufficient space to accommodate the additional side chain. In contrast, diaryl amino acids in the inverse agonist had considerable influence on receptor signaling. Whereas the introduction of Wsf maintains inverse agonism of the peptide, Wrf shifts the receptor more to active states and can induce agonism depending on its introduction site. John Wiley and Sons Inc. 2019-09-16 2019-11-06 /pmc/articles/PMC6899459/ /pubmed/31442005 http://dx.doi.org/10.1002/cmdc.201900409 Text en © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Full Papers Nicke, Lennart Müller, Ronny Geyer, Armin Els‐Heindl, Sylvia Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides |
title | Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides |
title_full | Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides |
title_fullStr | Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides |
title_full_unstemmed | Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides |
title_short | Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides |
title_sort | side chain orientation of tryptophan analogues determines agonism and inverse agonism in short ghrelin peptides |
topic | Full Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899459/ https://www.ncbi.nlm.nih.gov/pubmed/31442005 http://dx.doi.org/10.1002/cmdc.201900409 |
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