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

Authors :
Partho Protim Adhikary
Temilolu Idowu
Zheng Tan
Christopher Hoang
Selina Shanta
Malti Dumbani
Leah Mappalakayil
Bhuwan Awasthi
Marcel Bermudez
January Weiner
Dieter Beule
Gerhard Wolber
Brent DG Page
Sarah Hedtrich
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