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Disrupting TSLP–TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases
- Source :
- EMBO Molecular Medicine, Vol 16, Iss 7, Pp 1630-1656 (2024)
- Publication Year :
- 2024
- Publisher :
- Springer Nature, 2024.
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 17574684
- Volume :
- 16
- Issue :
- 7
- Database :
- Directory of Open Access Journals
- Journal :
- EMBO Molecular Medicine
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.6e1c32879ae240dfae3a2ec89df67bbc
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s44321-024-00085-3