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

  • EMBO Mol Med. 2024 Jul;16(7):1630-1656. doi: 10.1038/s44321-024-00085-3.
Partho Protim Adhikary  1 ,  Temilolu Idowu  1 ,  Zheng Tan  1 ,  Christopher Hoang  1 ,  Selina Shanta  1 ,  Malti Dumbani  2 ,  Leah Mappalakayil  1 ,  Bhuwan Awasthi  1 ,  Marcel Bermudez  2  3 ,  January Weiner  4 ,  Dieter Beule  4 ,  Gerhard Wolber  2 ,  Brent Dg Page  5 ,  Sarah Hedtrich  6  7  8  9
Affiliations
  • 1. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
  • 2. Institute of Pharmacy, Freie Universität of Berlin, Berlin, Germany.
  • 3. Institute of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität Münster, Münster, Germany.
  • 4. Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Germany Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • 5. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada. [email protected].
  • 6. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada. [email protected].
  • 7. Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Germany Charité - Universitätsmedizin Berlin, Berlin, Germany. [email protected].
  • 8. Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany. [email protected].
  • 9. Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany. [email protected].
PMID: 38877290 DOI: 10.1038/s44321-024-00085-3
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
Atopic Dermatitis; Atopic Diseases; Organ-on-chip; Small Molecule Inhibitor; TSLP.
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