A potent MAPK13-14 inhibitor prevents airway inflammation and mucus production
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.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:325 |
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| Enthalten in: |
American journal of physiology. Lung cellular and molecular physiology - 325(2023), 6 vom: 01. Dez., Seite L726-L740 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Keeler, Shamus P [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.11.2023 Date Revised 29.12.2023 published: Print-Electronic UpdateOf: bioRxiv. 2023 Oct 04;:. - PMID 37292761 Citation Status MEDLINE |
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| doi: |
10.1152/ajplung.00183.2023 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363402675 |
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| 100 | 1 | |a Keeler, Shamus P |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A potent MAPK13-14 inhibitor prevents airway inflammation and mucus production |
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| 500 | |a Date Revised 29.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2023 Oct 04;:. - PMID 37292761 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a asthma | |
| 650 | 4 | |a chronic obstructive pulmonary disease (COPD) | |
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| 700 | 1 | |a Wu, Kangyun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Dailing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Iberg, Courtney A |e verfasserin |4 aut | |
| 700 | 1 | |a Austin, Stephen R |e verfasserin |4 aut | |
| 700 | 1 | |a Glaser, Samuel A |e verfasserin |4 aut | |
| 700 | 1 | |a Yantis, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Podgorny, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Brody, Steven L |e verfasserin |4 aut | |
| 700 | 1 | |a Chartock, Joshua R |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Zhenfu |e verfasserin |4 aut | |
| 700 | 1 | |a Byers, Derek E |e verfasserin |4 aut | |
| 700 | 1 | |a Romero, Arthur G |e verfasserin |4 aut | |
| 700 | 1 | |a Holtzman, Michael J |e verfasserin |4 aut | |
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