Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides
| العنوان: | Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides |
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| المؤلفون: | Sylvia Els-Heindl, Armin Geyer, Lennart Nicke, Ronny Müller |
| المصدر: | Chemmedchem |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | ghrelin receptor, Stereochemistry, diaryl amino acids, Peptide, 01 natural sciences, Biochemistry, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Peptide synthesis, Inverse agonist, General Pharmacology, Toxicology and Pharmaceutics, Receptor, Receptors, Ghrelin, Solid-Phase Synthesis Techniques, Pharmacology, chemistry.chemical_classification, Indole test, Dose-Response Relationship, Drug, Molecular Structure, Full Paper, 010405 organic chemistry, Organic Chemistry, Tryptophan, Full Papers, Ghrelin, 0104 chemical sciences, Amino acid, 010404 medicinal & biomolecular chemistry, chemistry, peptides, Molecular Medicine, structure–activity relationships |
| الوصف: | We describe two synthetic amino acids with inverted side chain stereochemistry, which induce opposite biological activity. Phe4 is an important part of the activation motif of ghrelin, and in short peptide inverse agonists such as KwFwLL‐NH2, 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. Side chain orientation flips peptide behavior: Stereoisomeric diaryl amino acids substituting Phe4 in ghrelin were accepted with approximately 15‐fold activity loss. In a short inverse agonist, Wsf induced higher inverse agonist behavior than observed for Wrf‐containing analogues, with Wrf4 switching the peptide activity to agonism. |
| تدمد: | 1860-7187 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b82a9ab31226551cabe09a6ccfb619faTest https://pubmed.ncbi.nlm.nih.gov/31442005Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b82a9ab31226551cabe09a6ccfb619fa |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 18607187 |
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