Chemical Synthesis of TFF3 Reveals Novel Mechanistic Insights and a Gut-Stable Metabolite
| العنوان: | Chemical Synthesis of TFF3 Reveals Novel Mechanistic Insights and a Gut-Stable Metabolite |
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| المؤلفون: | Mark A. T. Blaskovich, Alysha G. Elliott, Christina I. Schroeder, Rajeshwari Meli, Séverine Morisset-Lopez, Hue N. T. Tran, Sabrina Spiller, Hayeon Baik, Nayara Braga Emidio, Markus Muttenthaler, Annette G. Beck-Sickinger |
| المساهمون: | University of Queensland [Brisbane], University of Vienna [Vienna], Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Universität Leipzig [Leipzig], National Institutes of Health [Bethesda] (NIH), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Frapart, Isabelle |
| المصدر: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2021, 64 (13), pp.9484-9495. ⟨10.1021/acs.jmedchem.1c00767⟩ Journal of Medicinal Chemistry, 2021, 64 (13), pp.9484-9495. ⟨10.1021/acs.jmedchem.1c00767⟩ |
| بيانات النشر: | HAL CCSD, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Protein Folding, Metabolite, [SDV]Life Sciences [q-bio], 01 natural sciences, Chemical synthesis, Biophysical Phenomena, Article, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Structure–activity relationship, Humans, Mode of action, 030304 developmental biology, 0303 health sciences, Molecular Structure, Oxidative folding, Native chemical ligation, 0104 chemical sciences, [SDV] Life Sciences [q-bio], 010404 medicinal & biomolecular chemistry, HEK293 Cells, Biochemistry, chemistry, Trefoil domain, Molecular Medicine, Protein folding, Trefoil Factor-3, Oxidation-Reduction |
| الوصف: | International audience; TFF3 regulates essential gastro- and neuroprotective functions, but its molecular mode of action remains poorly understood. Synthetic intractability and lack of reliable bioassays and validated receptors are bottlenecks for mechanistic and structure-activity relationship studies. Here, we report the chemical synthesis of TFF3 and its homodimer via native chemical ligation followed by oxidative folding. Correct folding was confirmed by NMR and circular dichroism, and TFF3 and its homodimer were not cytotoxic or hemolytic. TFF3, its homodimer, and the trefoil domain (TFF310-50) were susceptible to gastrointestinal degradation, revealing a gut-stable metabolite (TFF37-54; t1/2 > 24 h) that retained its trefoil structure and antiapoptotic bioactivity. We tried to validate the putative TFF3 receptors CXCR4 and LINGO2, but neither TFF3 nor its homodimer displayed any activity up to 10 μM. The discovery of a gut-stable bioactive metabolite and reliable synthetic accessibility to TFF3 and its analogues are cornerstones for future molecular probe development and structure-activity relationship studies. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0022-2623 1520-4804 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f8e711806df3a34b8bee790ad9eaf8c0 https://hal.archives-ouvertes.fr/hal-03335490 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f8e711806df3a34b8bee790ad9eaf8c0 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 00222623 15204804 |
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