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Chemical Synthesis of TFF3 Reveals Novel Mechanistic Insights and a Gut-Stable Metabolite

  1. Author:
    Emidio, Nayara Braga
    Meli, Rajeshwari
    Tran, Hue N. T.
    Baik, Hayeon
    Morisset-Lopez, Severine
    Elliott, Alysha G.
    Blaskovich, Mark A. T.
    Spiller, Sabrina
    Beck-Sickinger, Annette G.
    Schroeder,Christina
    Muttenthaler, Markus

  2. Author Address

    Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia.Univ Vienna, Fac Chem, Inst Biol Chem, A-1090 Vienna, Austria.Univ Orleans, Ctr Biophys Mol, Unite Propre Rech 4301, CNRS, F-45071 Orleans, France.Univ Leipzig, Fac Life Sci, Inst Biochem, D-04103 Leipzig, Germany.NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA.
    1. Year: 2021
    2. Date: Jul 8
  2. Journal: JOURNAL OF MEDICINAL CHEMISTRY
  3. AMER CHEMICAL SOC,
    1. 64
    2. 13
    3. Pages: 9484-9495
  5. Type of Article: Article
  6. ISSN: 0022-2623
  1. Abstract:

    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 (TFF3(10-50)) were susceptible to gastrointestinal degradation, revealing a gut-stable metabolite (TFF3(7-54); t(1/2) > 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 mu M. 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.

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External Sources

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  2. DOI: 10.1021/acs.jmedchem.1c00767
  3. View record in Web of Science®
  4. WOS: 000672729800037

Library Notes

  1. Fiscal Year: FY2020-2021
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