Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases

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.; Hedtrich, S.

Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases

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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 16(12):3247-3250.
Official Publication:	https://doi.org/10.1038/s44321-024-00085-3
PubMed:	View item in PubMed

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