| Autor: |
Shamus P. Keeler, Kangyun Wu, Yong Zhang, Dailing Mao, Ming Li, Courtney A. Iberg, Stephen R. Austin, Samuel A. Glaser, Jennifer Yantis, Stephanie Podgorny, Steven L. Brody, Joshua R. Chartock, Zhenfu Han, Derek E. Byers, Arthur G. Romero, Michael J. Holtzman |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
bioRxiv |
| Popis: |
Common respiratory diseases continue to represent a major public health problem, and much of the morbidity and mortality is due to airway inflammation and mucus production. Our previous work identified a mitogen-activated protein kinase (MAPK) known as MAPK13 that is activated in airway disease and is required for mucus production in human cell-culture models. However, only weak first-generation MAPK13 inhibitors were made to confirm gene-knockdown function, and there was no extension to effectiveness in vivo. Here we report the discovery of a first-in-class MAPK13 inhibitor (designated NuP-3) that down-regulates type-2 cytokine-stimulated mucus production in air-liquid interface and organoid cultures of human airway epithelial cells. We also show that NuP-3 treatment effectively attenuates respiratory inflammation and mucus production in new minipig models of airway disease after type-2 cytokine challenge or respiratory viral infection. Treatment also down-regulates biomarkers linked to basal-epithelial stem cell activation as an upstream site for target engagement. The results thereby provide proof-of-concept for a novel small-molecule kinase inhibitor to modify as yet uncorrected features of respiratory airway disease including stem cell reprogramming towards inflammation and mucus production. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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