De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8
Abstract The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have hig...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41272-z |
| _version_ | 1797558619987771392 |
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| author | Anindya Roy Lei Shi Ashley Chang Xianchi Dong Andres Fernandez John C. Kraft Jing Li Viet Q. Le Rebecca Viazzo Winegar Gerald Maxwell Cherf Dean Slocum P. Daniel Poulson Garrett E. Casper Mary L. Vallecillo-Zúniga Jonard Corpuz Valdoz Marcos C. Miranda Hua Bai Yakov Kipnis Audrey Olshefsky Tanu Priya Lauren Carter Rashmi Ravichandran Cameron M. Chow Max R. Johnson Suna Cheng McKaela Smith Catherine Overed-Sayer Donna K. Finch David Lowe Asim K. Bera Gustavo Matute-Bello Timothy P. Birkland Frank DiMaio Ganesh Raghu Jennifer R. Cochran Lance J. Stewart Melody G. Campbell Pam M. Van Ry Timothy Springer David Baker |
| author_facet | Anindya Roy Lei Shi Ashley Chang Xianchi Dong Andres Fernandez John C. Kraft Jing Li Viet Q. Le Rebecca Viazzo Winegar Gerald Maxwell Cherf Dean Slocum P. Daniel Poulson Garrett E. Casper Mary L. Vallecillo-Zúniga Jonard Corpuz Valdoz Marcos C. Miranda Hua Bai Yakov Kipnis Audrey Olshefsky Tanu Priya Lauren Carter Rashmi Ravichandran Cameron M. Chow Max R. Johnson Suna Cheng McKaela Smith Catherine Overed-Sayer Donna K. Finch David Lowe Asim K. Bera Gustavo Matute-Bello Timothy P. Birkland Frank DiMaio Ganesh Raghu Jennifer R. Cochran Lance J. Stewart Melody G. Campbell Pam M. Van Ry Timothy Springer David Baker |
| author_sort | Anindya Roy |
| collection | DOAJ |
| description | Abstract The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvβ6 and αvβ8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvβ6 and the αvβ8 integrins. In a lung fibrosis mouse model, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity. |
| first_indexed | 2024-03-10T17:34:02Z |
| format | Article |
| id | doaj.art-e3c311aafe5446188603fdc35eee2511 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:34:02Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e3c311aafe5446188603fdc35eee25112023-11-20T09:56:37ZengNature PortfolioNature Communications2041-17232023-09-0114111810.1038/s41467-023-41272-zDe novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8Anindya Roy0Lei Shi1Ashley Chang2Xianchi Dong3Andres Fernandez4John C. Kraft5Jing Li6Viet Q. Le7Rebecca Viazzo Winegar8Gerald Maxwell Cherf9Dean Slocum10P. Daniel Poulson11Garrett E. Casper12Mary L. Vallecillo-Zúniga13Jonard Corpuz Valdoz14Marcos C. Miranda15Hua Bai16Yakov Kipnis17Audrey Olshefsky18Tanu Priya19Lauren Carter20Rashmi Ravichandran21Cameron M. Chow22Max R. Johnson23Suna Cheng24McKaela Smith25Catherine Overed-Sayer26Donna K. Finch27David Lowe28Asim K. Bera29Gustavo Matute-Bello30Timothy P. Birkland31Frank DiMaio32Ganesh Raghu33Jennifer R. Cochran34Lance J. Stewart35Melody G. Campbell36Pam M. Van Ry37Timothy Springer38David Baker39Department of Biochemistry and Institute for Protein Design, University of WashingtonDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDepartment of Chemistry and Biochemistry, Brigham Young UniversityProgram in Cellular and Molecular Medicine, Children’s Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical SchoolDivision of Basic Sciences, Fred Hutchinson Cancer CenterDepartment of Biochemistry and Institute for Protein Design, University of WashingtonProgram in Cellular and Molecular Medicine, Children’s Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical SchoolProgram in Cellular and Molecular Medicine, Children’s Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical SchoolDepartment of Chemistry and Biochemistry, Brigham Young UniversityDepartment of Bioengineering, Stanford UniversityProgram in Cellular and Molecular Medicine, Children’s Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical SchoolDepartment of Chemistry and Biochemistry, Brigham Young UniversityDepartment of Chemistry and Biochemistry, Brigham Young UniversityDepartment of Chemistry and Biochemistry, Brigham Young UniversityDepartment of Chemistry and Biochemistry, Brigham Young UniversityDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDepartment of Materials Science and Engineering, University of WashingtonDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDepartment of Biochemistry and Institute for Protein Design, University of WashingtonResearch and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZenecaResearch and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZenecaResearch and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZenecaDepartment of Biochemistry and Institute for Protein Design, University of WashingtonCenter for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, University of WashingtonDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of WashingtonDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of WashingtonDepartment of Bioengineering, Stanford UniversityDepartment of Biochemistry and Institute for Protein Design, University of WashingtonDivision of Basic Sciences, Fred Hutchinson Cancer CenterDepartment of Chemistry and Biochemistry, Brigham Young UniversityProgram in Cellular and Molecular Medicine, Children’s Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical SchoolDepartment of Biochemistry and Institute for Protein Design, University of WashingtonAbstract The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvβ6 and αvβ8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvβ6 and the αvβ8 integrins. In a lung fibrosis mouse model, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.https://doi.org/10.1038/s41467-023-41272-z |
| spellingShingle | Anindya Roy Lei Shi Ashley Chang Xianchi Dong Andres Fernandez John C. Kraft Jing Li Viet Q. Le Rebecca Viazzo Winegar Gerald Maxwell Cherf Dean Slocum P. Daniel Poulson Garrett E. Casper Mary L. Vallecillo-Zúniga Jonard Corpuz Valdoz Marcos C. Miranda Hua Bai Yakov Kipnis Audrey Olshefsky Tanu Priya Lauren Carter Rashmi Ravichandran Cameron M. Chow Max R. Johnson Suna Cheng McKaela Smith Catherine Overed-Sayer Donna K. Finch David Lowe Asim K. Bera Gustavo Matute-Bello Timothy P. Birkland Frank DiMaio Ganesh Raghu Jennifer R. Cochran Lance J. Stewart Melody G. Campbell Pam M. Van Ry Timothy Springer David Baker De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8 Nature Communications |
| title | De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8 |
| title_full | De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8 |
| title_fullStr | De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8 |
| title_full_unstemmed | De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8 |
| title_short | De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8 |
| title_sort | de novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8 |
| url | https://doi.org/10.1038/s41467-023-41272-z |
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