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| Status |
Public on May 17, 2024 |
| Title |
Disrupting TSLP - TSLP receptor interactions via small molecule inhibitors yields a novel and efficient treatment option for atopic diseases |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Thymic stromal lymphopoietin (TSLP) is a key player in the pathogenesis of atopic diseases. Its pathophysiological relevance has sparked great interest in therapeutically targeting TSLP. Yet, so far, no small-mo lecule TSLP inhibitors exist due to the challenging nature of disrupting the protein-protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using structure- based 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 cytokine release at low micromolar concentrations. Topical application of BP79 yields efficient skin absorption followed by significant downregulation of atopy-relevant proinflammatory cytokines in immunocompetent skin disease models. For further analysis, we developed a human atopic disease drug discovery platform using microfluidic multi-organ chips. Here, topical application of BP79 onto atopic-like skin disease models that were co -cultivated with lung models in the presence of Th2 cells effectively suppressed immune cell infiltration and key atopy mediators including IL-13, IL-4, TSLP, and periostin, while upregulating skin barrier prote ins such as filaggrin. RNA-Seq analysis corroborated these findings and also indicated protective downstream effects on the lung epithelium. To the best of our knowledge, this represents the first report of a po tent and safe small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases. Further, it serves as a starting point for further developments in target ing TSLP as a central player of inflammation.
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| Overall design |
Two tissues (skin and lung) were divided between two 3D model conditions ("atopic-like" and normal) and then treated with BP79 compound or left untreated. Differential gene expression was used to infer regulated genes in either condition, and gene set enrichment analysis was used for discerning of relevant biological pathways
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| Web link |
https://www.embopress.org/doi/full/10.1038/s44321-024-00085-3
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| Contributor(s) |
Protim Adhikary P, Weiner J, Beule D, Hedtrich S |
| Citation(s) |
38877290 |
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| Submission date |
Apr 19, 2024 |
| Last update date |
Sep 09, 2024 |
| Contact name |
January 3rd Weiner |
| E-mail(s) |
january.weiner@gmail.com
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| Phone |
030450543049
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| Organization name |
Berlin Institute of Health, Charité Medical University of Berlin
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| Department |
CUBI
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| Street address |
Charitéplatz 1
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| City |
Berlin |
| ZIP/Postal code |
10117 |
| Country |
Germany |
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| Platforms (1) |
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| Samples (18)
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| GSM8218514 |
Brionchial epithelial tissue, normal-like model, untreated, replicate 20220412-R_S52 |
| GSM8218515 |
Skin tissue, normal-like model, untreated, replicate R_S51 |
| GSM8218516 |
Brionchial epithelial tissue, atopic-like model, treated with BP79, replicate 1_S3 |
| GSM8218517 |
Brionchial epithelial tissue, atopic-like model, treated with BP79, replicate 1_S9 |
| GSM8218518 |
Brionchial epithelial tissue, atopic-like model, treated with BP79, replicate 2_S10 |
| GSM8218519 |
Brionchial epithelial tissue, atopic-like model, treated with BP79, replicate 2_S4 |
| GSM8218520 |
Brionchial epithelial tissue, atopic-like model, untreated, replicate 1_S1 |
| GSM8218521 |
Brionchial epithelial tissue, atopic-like model, untreated, replicate 1_S7 |
| GSM8218522 |
Brionchial epithelial tissue, atopic-like model, untreated, replicate 2_S2 |
| GSM8218523 |
Brionchial epithelial tissue, atopic-like model, untreated, replicate 2_S8 |
| GSM8218524 |
Skin tissue, atopic-like model, treated with BP79, replicate 1_S10 |
| GSM8218525 |
Skin tissue, atopic-like model, treated with BP79, replicate 2_S11 |
| GSM8218526 |
Skin tissue, atopic-like model, untreated, replicate 1_S8 |
| GSM8218527 |
Skin tissue, atopic-like model, untreated, replicate 2_S9 |
| GSM8218528 |
Brionchial epithelial tissue, normal-like model, untreated, replicate 1_S12 |
| GSM8218529 |
Brionchial epithelial tissue, normal-like model, untreated, replicate 2_S13 |
| GSM8218530 |
Skin tissue, normal-like model, untreated, replicate 1_S6 |
| GSM8218531 |
Skin tissue, normal-like model, untreated, replicate 2_S7 |
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| Relations |
| BioProject |
PRJNA1102434 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE264457_raw_counts.tsv.gz |
1.1 Mb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
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