在人类纤维化模型中进行表型药物筛选，确定了一类新型抗纤维化疗法,Science Advances

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在人类纤维化模型中进行表型药物筛选，确定了一类新型抗纤维化疗法
Science Advances ( IF 11.7 ) Pub Date : 2021-12-01 , DOI: 10.1126/sciadv.abb3673
Michael Gerckens ₁ , Kenji Schorpp ₂ , Francesco Pelizza ₃ , Melanie Wögrath _{1,

4} , Kora Reichau _{5,

6} , Huilong Ma _{5,

6} , Armando-Marco Dworsky _{1,

4} , Arunima Sengupta ₁ , Mircea Gabriel Stoleriu _{1,

4,

7} , Katharina Heinzelmann _{8,

9} , Juliane Merl-Pham ₁₀ , Martin Irmler ₁₁ , Hani N Alsafadi _{4,

9,

12} , Eduard Trenkenschuh ₁₃ , Lenka Sarnova ₁₄ , Marketa Jirouskova ₁₄ , Wolfgang Frieß ₁₃ , Stefanie M Hauck ₁₀ , Johannes Beckers _{11,

15,

16} , Nikolaus Kneidinger _{4,

17} , Jürgen Behr _{4,

7,

17} , Anne Hilgendorff _{1,

4} , Kamyar Hadian ₂ , Michael Lindner _{4,

7,

18} , Melanie Königshoff _{8,

9} , Oliver Eickelberg ₈ , Martin Gregor ₁₄ , Oliver Plettenburg _{5,

6,

19} , Ali Önder Yildirim ₁ , Gerald Burgstaller _{1,

4}

Affiliation

Institute of Lung Biology and Disease (ILBD) and Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Chemical and Process Engineering, Strathclyde University, Glasgow, Scotland, UK.
CPC-M bioArchive, Helmholtz Zentrum München, Comprehensive Pneumology Center Munich DZL/CPC-M, Munich, Germany.
Institute of Medicinal Chemistry, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
Leibniz Universität Hannover, Institute of Organic Chemistry and Center for Biomolecular Drug Research (BMWZ), Hannover, Germany.
Asklepios Fachkliniken Munich-Gauting, Munich, Germany.
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Comprehensive Pneumology Center (CPC), Research Unit Lung Repair and Regeneration, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Wallenberg Center for Molecular Medicine (WCMM), Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
Department of Pharmacy-Center for Drug Research, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximillians University of Munich, Munich, Germany.
Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany.
Chair of Experimental Genetics, Technische Universität München, 85354 Freising, Germany.
Department of Internal Medicine V, Ludwig-Maximillians University of Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.
Paracelsus Medical Private University, Salzburg, Austria.
Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany.

纤维化过程引发致命的慢性疾病，导致器官衰竭和死亡。潜在的生物过程涉及异常成纤维细胞引起的细胞外基质 (ECM) 的大量沉积。我们对患病的原代人肺成纤维细胞进行了先进的三维表型高内涵分析，并筛选了用于抑制 ECM 沉积的小分子再利用药物库。通过人工智能进行的纤维化模式检测将曲尼司特确定为一种有效的抑制剂。构效关系研究证实N-(2-丁氧基苯基)-3-(苯基)丙烯酰胺 (N23Ps) 作为一种新型高效化合物。N23Ps 抑制肌成纤维细胞转分化、ECM 沉积、细胞收缩性和改变细胞形状，从而提倡一种独特的作用模式。从机制上讲，转录组学将 SMURF2 确定为潜在的治疗靶点网络。N23Ps 的抗纤维化活性通过蛋白质组学在人类离体组织纤维化疾病模型中得到验证，抑制促纤维化标记物 SERPINE1 和 CXCL8。总之，N23Ps 是一类新型的高效化合物，可抑制患者的器官纤维化。

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更新日期：2021-12-22

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