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Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation
Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of my...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677786/ https://www.ncbi.nlm.nih.gov/pubmed/34916483 http://dx.doi.org/10.1038/s41419-021-04439-4 |
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author | Ring, Nadja Anneliese Ruth Volpe, Maria Concetta Stepišnik, Tomaž Mamolo, Maria Grazia Panov, Panče Kocev, Dragi Vodret, Simone Fortuna, Sara Calabretti, Antonella Rehman, Michael Colliva, Andrea Marchesan, Pietro Camparini, Luca Marcuzzo, Thomas Bussani, Rossana Scarabellotto, Sara Confalonieri, Marco Pham, Tho X. Ligresti, Giovanni Caporarello, Nunzia Loffredo, Francesco S. Zampieri, Daniele Džeroski, Sašo Zacchigna, Serena |
author_facet | Ring, Nadja Anneliese Ruth Volpe, Maria Concetta Stepišnik, Tomaž Mamolo, Maria Grazia Panov, Panče Kocev, Dragi Vodret, Simone Fortuna, Sara Calabretti, Antonella Rehman, Michael Colliva, Andrea Marchesan, Pietro Camparini, Luca Marcuzzo, Thomas Bussani, Rossana Scarabellotto, Sara Confalonieri, Marco Pham, Tho X. Ligresti, Giovanni Caporarello, Nunzia Loffredo, Francesco S. Zampieri, Daniele Džeroski, Sašo Zacchigna, Serena |
author_sort | Ring, Nadja Anneliese Ruth |
collection | PubMed |
description | Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice. High-throughput screens are an ideal method of repurposing drugs, yet they contain an intrinsic limitation, which is the size of the library itself. Here, we exploited the data from our “wet” screen and used “dry” machine learning analysis to virtually screen millions of compounds, identifying novel anti-fibrotic hits which target myofibroblast differentiation, many of which were structurally related to dopamine. We synthesized and validated several compounds ex vivo (“wet”) and confirmed that both dopamine and its derivative TS1 are powerful inhibitors of myofibroblast activation. We further used RNAi-mediated knock-down and demonstrated that both molecules act through the dopamine receptor 3 and exert their anti-fibrotic effect by inhibiting the canonical transforming growth factor β pathway. Furthermore, molecular modelling confirmed the capability of TS1 to bind both human and mouse dopamine receptor 3. The anti-fibrotic effect on human cells was confirmed using primary fibroblasts from idiopathic pulmonary fibrosis patients. Finally, TS1 prevented and reversed disease progression in a murine model of lung fibrosis. Both our interdisciplinary approach and our novel compound TS1 are promising tools for understanding and combating lung fibrosis. |
format | Online Article Text |
id | pubmed-8677786 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86777862022-01-04 Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation Ring, Nadja Anneliese Ruth Volpe, Maria Concetta Stepišnik, Tomaž Mamolo, Maria Grazia Panov, Panče Kocev, Dragi Vodret, Simone Fortuna, Sara Calabretti, Antonella Rehman, Michael Colliva, Andrea Marchesan, Pietro Camparini, Luca Marcuzzo, Thomas Bussani, Rossana Scarabellotto, Sara Confalonieri, Marco Pham, Tho X. Ligresti, Giovanni Caporarello, Nunzia Loffredo, Francesco S. Zampieri, Daniele Džeroski, Sašo Zacchigna, Serena Cell Death Dis Article Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice. High-throughput screens are an ideal method of repurposing drugs, yet they contain an intrinsic limitation, which is the size of the library itself. Here, we exploited the data from our “wet” screen and used “dry” machine learning analysis to virtually screen millions of compounds, identifying novel anti-fibrotic hits which target myofibroblast differentiation, many of which were structurally related to dopamine. We synthesized and validated several compounds ex vivo (“wet”) and confirmed that both dopamine and its derivative TS1 are powerful inhibitors of myofibroblast activation. We further used RNAi-mediated knock-down and demonstrated that both molecules act through the dopamine receptor 3 and exert their anti-fibrotic effect by inhibiting the canonical transforming growth factor β pathway. Furthermore, molecular modelling confirmed the capability of TS1 to bind both human and mouse dopamine receptor 3. The anti-fibrotic effect on human cells was confirmed using primary fibroblasts from idiopathic pulmonary fibrosis patients. Finally, TS1 prevented and reversed disease progression in a murine model of lung fibrosis. Both our interdisciplinary approach and our novel compound TS1 are promising tools for understanding and combating lung fibrosis. Nature Publishing Group UK 2021-12-17 /pmc/articles/PMC8677786/ /pubmed/34916483 http://dx.doi.org/10.1038/s41419-021-04439-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ring, Nadja Anneliese Ruth Volpe, Maria Concetta Stepišnik, Tomaž Mamolo, Maria Grazia Panov, Panče Kocev, Dragi Vodret, Simone Fortuna, Sara Calabretti, Antonella Rehman, Michael Colliva, Andrea Marchesan, Pietro Camparini, Luca Marcuzzo, Thomas Bussani, Rossana Scarabellotto, Sara Confalonieri, Marco Pham, Tho X. Ligresti, Giovanni Caporarello, Nunzia Loffredo, Francesco S. Zampieri, Daniele Džeroski, Sašo Zacchigna, Serena Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation |
title | Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation |
title_full | Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation |
title_fullStr | Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation |
title_full_unstemmed | Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation |
title_short | Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation |
title_sort | wet-dry-wet drug screen leads to the synthesis of ts1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677786/ https://www.ncbi.nlm.nih.gov/pubmed/34916483 http://dx.doi.org/10.1038/s41419-021-04439-4 |
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