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| Item Type: | Article |
|---|---|
| Title: | Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases |
| Creators Name: | Adhikary, P.P. and Idowu, T. and Tan, Z. and Hoang, C. and Shanta, S. and Dumbani, M. and Mappalakayil, L. and Awasthi, B. and Bermudez, M. and Weiner, J. and Beule, D. and Wolber, G. and Page, B.D. and Hedtrich, S. |
| Abstract: | Thymic stromal lymphopoietin (TSLP) is a key player in atopic diseases, which has sparked great interest in therapeutically targeting TSLP. Yet, no small-molecule TSLP inhibitors exist due to the challenges of disrupting the protein-protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using virtual screening and docking of >1,000,000 compounds followed by iterative chemical synthesis. BP79 emerged as our lead compound that effectively abrogates TSLP-triggered cytokines at low micromolar concentrations. For in-depth analysis, we developed a human atopic disease drug discovery platform using multi-organ chips. Here, topical application of BP79 onto atopic skin models that were co-cultivated with lung models and Th2 cells effectively suppressed immune cell infiltration and IL-13, IL-4, TSLP, and periostin secretion, while upregulating skin barrier proteins. RNA-Seq analysis corroborate these findings and indicate protective downstream effects on the lungs. To the best of our knowledge, this represents the first report of a potent putative small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases. |
| Keywords: | TSLP, Atopic Diseases, Atopic Dermatitis, Organ-on-chip, Small Molecule Inhibitor, Animals, Mice |
| Source: | EMBO Molecular Medicine |
| ISSN: | 1757-4676 |
| Publisher: | EMBO Press / Wiley |
| Date: | 14 June 2024 |
| Official Publication: | https://doi.org/10.1038/s44321-024-00085-3 |
| PubMed: | View item in PubMed |
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