Back to Search Start Over

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

Authors :
Braga Emidio N
Meli R
Tran HNT
Baik H
Morisset-Lopez S
Elliott AG
Blaskovich MAT
Spiller S
Beck-Sickinger AG
Schroeder CI
Muttenthaler M
Source :
Journal of medicinal chemistry [J Med Chem] 2021 Jul 08; Vol. 64 (13), pp. 9484-9495. Date of Electronic Publication: 2021 Jun 18.
Publication Year :
2021

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

Details

Language :
English
ISSN :
1520-4804
Volume :
64
Issue :
13
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
34142550
Full Text :
https://doi.org/10.1021/acs.jmedchem.1c00767