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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., Idowu, T., Tan, Z., Hoang, C., Shanta, S., Dumbani, M., Mappalakayil, L., Awasthi, B., Bermudez, M., Weiner, J., Beule, D., Wolber, G., 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 |
| Source: | EMBO Molecular Medicine |
| ISSN: | 1757-4676 |
| Publisher: | EMBO Press / Wiley |
| Volume: | 16 |
| Number: | 7 |
| Page Range: | 1630-1656 |
| Date: | 15 July 2024 |
| Additional Information: | Erratum in: EMBO Mol Med 2024 Nov 7. |
| Official Publication: | https://doi.org/10.1038/s44321-024-00085-3 |
| PubMed: | View item in PubMed |
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