| Autor: |
Mahshid Gazorpak, Karina M. Hugentobler, Dominique Paul, Pierre-Luc Germain, Miriam Kretschmer, Iryna Ivanova, Selina Frei, Kei Mathis, Remo Rudolf, Sergio Mompart Barrenechea, Vincent Fischer, Xiaohan Xue, Aleksandra L. Ptaszek, Julian Holzinger, Mattia Privitera, Andreas Hierlemann, Onno C. Meijer, Robert Konrat, Erick M. Carreira, Johannes Bohacek, Katharina Gapp |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 14, Iss 1, Pp 1-23 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-023-44031-2 |
| Popis: |
Abstract Counteracting the overactivation of glucocorticoid receptors (GR) is an important therapeutic goal in stress-related psychiatry and beyond. The only clinically approved GR antagonist lacks selectivity and induces unwanted side effects. To complement existing tools of small-molecule-based inhibitors, we present a highly potent, catalytically-driven GR degrader, KH-103, based on proteolysis-targeting chimera technology. This selective degrader enables immediate and reversible GR depletion that is independent of genetic manipulation and circumvents transcriptional adaptations to inhibition. KH-103 achieves passive inhibition, preventing agonistic induction of gene expression, and significantly averts the GR’s genomic effects compared to two currently available inhibitors. Application in primary-neuron cultures revealed the dependency of a glucocorticoid-induced increase in spontaneous calcium activity on GR. Finally, we present a proof of concept for application in vivo. KH-103 opens opportunities for a more lucid interpretation of GR functions with translational potential. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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