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Published on: March 2, 2016
A potent MAPK13-14 inhibitor prevents airway inflammation and mucus production
Shamus P Keeler1, Kangyun Wu1, Yong Zhang1
1Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States.
Abstract:
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. Previous studies indicated a role for mitogen-activated protein kinase 14 (MAPK14) in this type of disease, but clinical trials are unsuccessful to date. Our previous work identified a related but distinct kinase known as MAPK13 that is activated in respiratory airway diseases and is required for mucus production in human cell-culture models. Support for MAPK13 function in these models came from effectiveness of MAPK13 versus MAPK14 gene-knockdown and from first-generation MAPK13-14 inhibitors. However, these first-generation inhibitors were incompletely optimized for blocking activity and were untested in vivo. Here we report the next generation and selection of a potent MAPK13-14 inhibitor (designated NuP-3) that more effectively downregulates 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 prevents respiratory airway inflammation and mucus production in new minipig models of airway disease triggered by type-2 cytokine challenge or respiratory viral infection. The results thereby provide the next advance in developing a small-molecule kinase inhibitor to address key features of respiratory disease.NEW & NOTEWORTHY This study describes the discovery of a potent mitogen-activated protein kinase 13-14 (MAPK13-14) inhibitor and its effectiveness in models of respiratory airway disease. The findings thereby provide a scheme for pathogenesis and therapy of lung diseases [e.g., asthma, chronic obstructive pulmonary disease (COPD), Covid-19, postviral, and allergic respiratory disease] and related conditions that implicate MAPK13-14 function. The findings also refine a hypothesis for epithelial and immune cell functions in respiratory disease that features MAPK13 as a possible component of this disease process.
Insights
Researchers developed a new inhibitor targeting MAPK13-14 to reduce airway inflammation and mucus production, offering a potential therapy for respiratory diseases like asthma and COPD.
Area of Science:
- Molecular biology
- Immunology
- Respiratory medicine
Background:
- Airway inflammation and mucus overproduction are hallmarks of common respiratory diseases.
- Mitogen-activated protein kinase 14 (MAPK14) has been implicated, but clinical trials failed.
- Mitogen-activated protein kinase 13 (MAPK13) is activated in airway diseases and crucial for mucus production.
Purpose of the Study:
- To develop and evaluate a potent MAPK13-14 inhibitor for treating respiratory diseases.
- To assess the inhibitor's efficacy in reducing mucus production and inflammation in vitro and in vivo.
Main Methods:
- Developed a next-generation MAPK13-14 inhibitor (NuP-3).
- Tested NuP-3 in human airway epithelial cell cultures (air-liquid interface and organoids).
- Evaluated NuP-3 in minipig models of respiratory airway disease induced by cytokine challenge or viral infection.
Main Results:
- NuP-3 significantly reduced type-2 cytokine-stimulated mucus production in human airway cell models.
- NuP-3 treatment prevented respiratory airway inflammation and mucus production in minipig models.
- Demonstrated the inhibitor's effectiveness in both in vitro and in vivo models of respiratory disease.
Conclusions:
- A potent MAPK13-14 inhibitor (NuP-3) effectively targets key features of respiratory diseases.
- Findings support MAPK13-14 as a therapeutic target for lung diseases such as asthma, COPD, and COVID-19.
- The study refines understanding of epithelial and immune cell roles in respiratory disease pathogenesis.
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