Computational design of diverse nuclear factor erythroid 2 activators with cellular antioxidative activity
Summary: Oxidative stress disrupts signaling pathways contributing to chronic diseases, while the KEAP1-NRF2 pathway is central to cellular antioxidant defenses. Current synthetic antioxidants struggle to activate this pathway efficiently or selectively. In this study, we employed deep learning algo...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-06-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422500882X |
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| author | Mingyue Yuwen Xiaoning Gao Junli Ba Jiayang Wu Jun Kang Sheng Ye Cheng Zhu |
| author_facet | Mingyue Yuwen Xiaoning Gao Junli Ba Jiayang Wu Jun Kang Sheng Ye Cheng Zhu |
| author_sort | Mingyue Yuwen |
| collection | DOAJ |
| description | Summary: Oxidative stress disrupts signaling pathways contributing to chronic diseases, while the KEAP1-NRF2 pathway is central to cellular antioxidant defenses. Current synthetic antioxidants struggle to activate this pathway efficiently or selectively. In this study, we employed deep learning algorithms to design miniproteins capable of activating NRF2. Five designed binders potently interfered with the KEAP1-NRF2 complex, exhibiting affinities ranging from 4.4 nM to 53.3 nM toward KEAP1. Two of these binders, designed through the motif scaffolding method, activated NRF2 in eukaryotic cells increasing antioxidant gene expression 3.8-fold and boosting cell survival across oxidative stress levels. Our approach illustrates the potential of integrated deep learning models to develop stable miniproteins that exhibit a variety of structural frameworks and thermodynamic characteristics. These designs hold promise for countering the cumulative effects of oxidative damage and for supporting the establishment of adaptive homeostasis within key antioxidative systems. |
| format | Article |
| id | doaj-art-ef3f413f430c4058b29fc9a9be6c1928 |
| institution | OA Journals |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-ef3f413f430c4058b29fc9a9be6c19282025-08-20T02:30:10ZengElsevieriScience2589-00422025-06-0128611262110.1016/j.isci.2025.112621Computational design of diverse nuclear factor erythroid 2 activators with cellular antioxidative activityMingyue Yuwen0Xiaoning Gao1Junli Ba2Jiayang Wu3Jun Kang4Sheng Ye5Cheng Zhu6State Key Laboratory of Synthetic Biology, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, ChinaState Key Laboratory of Synthetic Biology, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, ChinaState Key Laboratory of Synthetic Biology, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, ChinaState Key Laboratory of Synthetic Biology, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, ChinaState Key Laboratory of Synthetic Biology, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China; Corresponding authorState Key Laboratory of Synthetic Biology, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China; Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, China; Corresponding authorState Key Laboratory of Synthetic Biology, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China; Corresponding authorSummary: Oxidative stress disrupts signaling pathways contributing to chronic diseases, while the KEAP1-NRF2 pathway is central to cellular antioxidant defenses. Current synthetic antioxidants struggle to activate this pathway efficiently or selectively. In this study, we employed deep learning algorithms to design miniproteins capable of activating NRF2. Five designed binders potently interfered with the KEAP1-NRF2 complex, exhibiting affinities ranging from 4.4 nM to 53.3 nM toward KEAP1. Two of these binders, designed through the motif scaffolding method, activated NRF2 in eukaryotic cells increasing antioxidant gene expression 3.8-fold and boosting cell survival across oxidative stress levels. Our approach illustrates the potential of integrated deep learning models to develop stable miniproteins that exhibit a variety of structural frameworks and thermodynamic characteristics. These designs hold promise for countering the cumulative effects of oxidative damage and for supporting the establishment of adaptive homeostasis within key antioxidative systems.http://www.sciencedirect.com/science/article/pii/S258900422500882XMolecular interactionBiomolecular engineeringProtein structure aspects |
| spellingShingle | Mingyue Yuwen Xiaoning Gao Junli Ba Jiayang Wu Jun Kang Sheng Ye Cheng Zhu Computational design of diverse nuclear factor erythroid 2 activators with cellular antioxidative activity iScience Molecular interaction Biomolecular engineering Protein structure aspects |
| title | Computational design of diverse nuclear factor erythroid 2 activators with cellular antioxidative activity |
| title_full | Computational design of diverse nuclear factor erythroid 2 activators with cellular antioxidative activity |
| title_fullStr | Computational design of diverse nuclear factor erythroid 2 activators with cellular antioxidative activity |
| title_full_unstemmed | Computational design of diverse nuclear factor erythroid 2 activators with cellular antioxidative activity |
| title_short | Computational design of diverse nuclear factor erythroid 2 activators with cellular antioxidative activity |
| title_sort | computational design of diverse nuclear factor erythroid 2 activators with cellular antioxidative activity |
| topic | Molecular interaction Biomolecular engineering Protein structure aspects |
| url | http://www.sciencedirect.com/science/article/pii/S258900422500882X |
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