Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics.
Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics.
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人类纤维化模型中的表型药物筛选确定了一类新型的抗纤维化疗法。
DOI：
10.1126/sciadv.abb3673
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发表时间：
2021-12-24
期刊：
影响因子：
13.6
通讯作者：
Burgstaller G
中科院分区：
文献类型：
--
作者：
Gerckens M;Schorpp K;Pelizza F;Wögrath M;Reichau K;Ma H;Dworsky AM;Sengupta A;Stoleriu MG;Heinzelmann K;Merl-Pham J;Irmler M;Alsafadi HN;Trenkenschuh E;Sarnova L;Jirouskova M;Frieß W;Hauck SM;Beckers J;Kneidinger N;Behr J;Hilgendorff A;Hadian K;Lindner M;Königshoff M;Eickelberg O;Gregor M;Plettenburg O;Yildirim AÖ;Burgstaller G
创新的高内涵筛选平台将N-（2-丁氧基苯基）-3-（苯基）丙烯酰胺鉴定为新型抗纤维化药物。纤维化过程引发致命的慢性疾病，导致器官衰竭和死亡。潜在的生物学过程涉及异常成纤维细胞诱导的细胞外基质（ECM）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含量测定，并筛选了用于抑制ECM沉积的小分子再利用药物库。人工智能纤维化模式检测将曲尼司特确定为有效的抑制剂。构效关系研究证实N-（2-丁氧基苯基）-3-（苯基）丙烯酰胺（N23 Ps）是一类新型高效化合物。N23 Ps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，从而倡导独特的作用模式。从机制上讲，转录组学将SMURF 2确定为潜在的治疗靶点网络。通过蛋白质组学在人离体组织纤维化疾病模型中验证N23 Ps的抗纤维化活性，抑制促纤维化标志物SERPINE 1和CXCL 8。总之，N23 Ps是一类新型的高效化合物，可抑制患者的器官纤维化。
Innovative high-content screening platform identified N-(2-butoxyphenyl)-3-(phenyl)acrylamides as novel antifibrotics. 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.
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影响因子：
64.8
作者：
BORDER, WA;NOBLE, NA;RUOSLAHTI, E
通讯作者：
RUOSLAHTI, E
DOI：
10.1152/ajplung.00408.2017
发表时间：
2018-05-01
影响因子：
4.9
作者：
Burgstaller, Gerald;Sengupta, Arunima;Eickelberg, Oliver
通讯作者：
Eickelberg, Oliver
影响因子：
3.7
作者：
Burgstaller G;Oehrle B;Koch I;Lindner M;Eickelberg O
通讯作者：
Eickelberg O
影响因子：
4.6
作者：
Chen CL;Mahjoubfar A;Tai LC;Blaby IK;Huang A;Niazi KR;Jalali B
通讯作者：
Jalali B
影响因子：
4.3
作者：
Cox TR;Erler JT
通讯作者：
Erler JT