Chartock, J. R. | bioRxiv Science

bioRxiv2024

A first-in-kind MAPK13 inhibitor that can correct stem cell reprogramming and post-injury disease

The stress kinase MAPK13 (aka p38delta-MAPK) is an attractive entry point for therapeutic intervention because it regulates the structural remodeling that can develop after epithelial injury in the lung and likely other tissue sites. However, a selective, safe, and effective MAPK13 inhibitor is not yet available for experimental or clinical application. Here we identify a first-in-kind MAPK13 inhibitor using structure-based drug design combined with a screening funnel for cell safety and molecular specificity. In a mouse model of severe respiratory viral infection, treatment with this inhibitor (formulated as NuP-4A for intravenous use or Nu4-B for inhaled delivery) did not influence recovery from acute infectious illness, but still down-regulated basal-epithelial stem cell (basal-ESC) hyperplasia/metaplasia and in turn airway inflammation, mucus production, and pathophysiology biomarkers of chronic lung disease. Treatment prevented and reversed disease readouts equivalently to Mapk13 gene-knockout, and this benefit persisted after stopping treatment as a sign of disease modification. Further, NuP-4 treatment even at pM levels directly blocked basal-ESC reprogramming endpoints in organoid and cell-culture models derived from non-disease control and asthma subjects. The results thereby provide a new tool compound and drug candidate for basal-ESC reprogramming towards muco-obstructive lung diseases like asthma and any overlap with COPD and related diseases that depend on overactivity of MAPK13.

immunology↗

bioRxiv2023

A new MAPK13-guided inhibitor for respiratory 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 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 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 and noteworthyThis study describes the discovery of a potent 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, COPD, Covid-19, post-viral 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.

immunology↗