Gerckens, M.; Schorpp, K.; Pelizza, F.; Wögrath, M.; Reichau, K. et al.: Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics. In: Science Advances 7 (2021), Nr. 52, eabb3673. DOI: https://doi.org/10.1126/sciadv.abb3673
Abstract: | |
Fibrogenic processes instigate fatal chronic diseases leading to organ failure and death. Underlying biological processes involve induced massive deposition of extracellular matrix (ECM) by aberrant fibroblasts. We subjected diseased primary human lung fibroblasts to an advanced three-dimensional phenotypic high-content assay and screened a repurposing drug library of small molecules for inhibiting ECM deposition. Fibrotic Pattern Detection by Artificial Intelligence identified tranilast as an effective inhibitor. Structure-activity relationship studies confirmed N-(2-butoxyphenyl)-3-(phenyl)acrylamides (N23Ps) as a novel and highly potent compound class. N23Ps suppressed myofibroblast transdifferentiation, ECM deposition, cellular contractility, and altered cell shapes, thus advocating a unique mode of action. Mechanistically, transcriptomics identified SMURF2 as a potential therapeutic target network. Antifibrotic activity of N23Ps was verified by proteomics in a human ex vivo tissue fibrosis disease model, suppressing profibrotic markers SERPINE1 and CXCL8. Conclusively, N23Ps are a novel class of highly potent compounds inhibiting organ fibrosis in patients. | |
License of this version: | CC BY-NC 4.0 Unported |
Document Type: | Article |
Publishing status: | publishedVersion |
Issue Date: | 2021 |
Appears in Collections: | Naturwissenschaftliche Fakultät Forschungszentren |
pos. | country | downloads | ||
---|---|---|---|---|
total | perc. | |||
1 | Germany | 10 | 45.45% | |
2 | United States | 6 | 27.27% | |
3 | Switzerland | 2 | 9.09% | |
4 | Russian Federation | 1 | 4.55% | |
5 | Sri Lanka | 1 | 4.55% | |
6 | India | 1 | 4.55% | |
7 | Europe | 1 | 4.55% |
Hinweis
Zur Erhebung der Downloadstatistiken kommen entsprechend dem „COUNTER Code of Practice for e-Resources“ international anerkannte Regeln und Normen zur Anwendung. COUNTER ist eine internationale Non-Profit-Organisation, in der Bibliotheksverbände, Datenbankanbieter und Verlage gemeinsam an Standards zur Erhebung, Speicherung und Verarbeitung von Nutzungsdaten elektronischer Ressourcen arbeiten, welche so Objektivität und Vergleichbarkeit gewährleisten sollen. Es werden hierbei ausschließlich Zugriffe auf die entsprechenden Volltexte ausgewertet, keine Aufrufe der Website an sich.