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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\n                  <jats:italic>Mapk13<\/jats:italic>\n                  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.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>New and noteworthy<\/jats:title>\n                  <jats:p>This study identifies to our knowledge a first highly selective and potent small-molecule inhibitor (designated NuP-4) to target stress kinase MAPK13. The results also demonstrate that NuP-4 treatment preserves homeostatic defense and repair but prevents excessive basal-ESC responses to respiratory viral infection and thereby attenuates key biomarkers of chronic lung disease in mouse and human models. The findings provide guidance for precise therapeutic application in asthma and related diseases that are triggered by respiratory viruses and other airborne hazards. The tissue distribution of MAPK13 implies related applications at other epithelial sites.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.08.21.608990","type":"posted-content","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T17:20:20Z","timestamp":1724347220000},"source":"Crossref","is-referenced-by-count":4,"title":["A first-in-kind MAPK13 inhibitor corrects epithelial stem cell reprogramming and muco-obstructive lung disease"],"prefix":"10.64898","author":[{"given":"Yong","family":"Zhang","sequence":"first","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangyun","family":"Wu","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO 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