De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist
Summary: Lasso-grafting (LG) technology is a method for generating de novo biologics (neobiologics) by genetically implanting macrocyclic peptide pharmacophores, which are selected in vitro against a protein of interest, into loops of arbitrary protein scaffolds. In this study, we have generated a n...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-11-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004221012712 |
| _version_ | 1818927843640344576 |
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| author | Yamato Komatsu Naohiro Terasaka Katsuya Sakai Emiko Mihara Risa Wakabayashi Kunio Matsumoto Donald Hilvert Junichi Takagi Hiroaki Suga |
| author_facet | Yamato Komatsu Naohiro Terasaka Katsuya Sakai Emiko Mihara Risa Wakabayashi Kunio Matsumoto Donald Hilvert Junichi Takagi Hiroaki Suga |
| author_sort | Yamato Komatsu |
| collection | DOAJ |
| description | Summary: Lasso-grafting (LG) technology is a method for generating de novo biologics (neobiologics) by genetically implanting macrocyclic peptide pharmacophores, which are selected in vitro against a protein of interest, into loops of arbitrary protein scaffolds. In this study, we have generated a neo-capsid that potently binds the hepatocyte growth factor receptor MET by LG of anti-MET peptide pharmacophores into a circularly permuted variant of Aquifex aeolicus lumazine synthase (AaLS), a self-assembling protein nanocapsule. By virtue of displaying multiple-pharmacophores on its surface, the neo-capsid can induce dimerization (or multimerization) of MET, resulting in phosphorylation and endosomal internalization of the MET-capsid complex. This work demonstrates the potential of the LG technology as a synthetic biology approach for generating capsid-based neobiologics capable of activating signaling receptors. |
| first_indexed | 2024-12-20T03:19:27Z |
| format | Article |
| id | doaj.art-f66388c0f64b4cedba1f72a4ac812d78 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-20T03:19:27Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-f66388c0f64b4cedba1f72a4ac812d782022-12-21T19:55:15ZengElsevieriScience2589-00422021-11-012411103302De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonistYamato Komatsu0Naohiro Terasaka1Katsuya Sakai2Emiko Mihara3Risa Wakabayashi4Kunio Matsumoto5Donald Hilvert6Junichi Takagi7Hiroaki Suga8Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanDepartment of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding authorDivision of Tumor Dynamics and Regulation, Cancer Research Institute, and WPI-Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma, Kanazawa-shi, Ishikawa 920-1192, JapanLaboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita-shi, Osaka 565-0871, JapanDepartment of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanDivision of Tumor Dynamics and Regulation, Cancer Research Institute, and WPI-Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma, Kanazawa-shi, Ishikawa 920-1192, JapanLaboratory of Organic Chemistry, ETH Zürich, 8093 Zürich, SwitzerlandLaboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita-shi, Osaka 565-0871, JapanDepartment of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding authorSummary: Lasso-grafting (LG) technology is a method for generating de novo biologics (neobiologics) by genetically implanting macrocyclic peptide pharmacophores, which are selected in vitro against a protein of interest, into loops of arbitrary protein scaffolds. In this study, we have generated a neo-capsid that potently binds the hepatocyte growth factor receptor MET by LG of anti-MET peptide pharmacophores into a circularly permuted variant of Aquifex aeolicus lumazine synthase (AaLS), a self-assembling protein nanocapsule. By virtue of displaying multiple-pharmacophores on its surface, the neo-capsid can induce dimerization (or multimerization) of MET, resulting in phosphorylation and endosomal internalization of the MET-capsid complex. This work demonstrates the potential of the LG technology as a synthetic biology approach for generating capsid-based neobiologics capable of activating signaling receptors.http://www.sciencedirect.com/science/article/pii/S2589004221012712PeptidesBiotechnologySynthetic biology |
| spellingShingle | Yamato Komatsu Naohiro Terasaka Katsuya Sakai Emiko Mihara Risa Wakabayashi Kunio Matsumoto Donald Hilvert Junichi Takagi Hiroaki Suga De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist iScience Peptides Biotechnology Synthetic biology |
| title | De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist |
| title_full | De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist |
| title_fullStr | De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist |
| title_full_unstemmed | De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist |
| title_short | De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist |
| title_sort | de novo peptide grafting to a self assembling nanocapsule yields a hepatocyte growth factor receptor agonist |
| topic | Peptides Biotechnology Synthetic biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004221012712 |
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