Nature Communications (Sep 2023)
De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8
- 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
Affiliations
- Anindya Roy
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Lei Shi
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Ashley Chang
- Department of Chemistry and Biochemistry, Brigham Young University
- Xianchi Dong
- Program in Cellular and Molecular Medicine, Children’s Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School
- Andres Fernandez
- Division of Basic Sciences, Fred Hutchinson Cancer Center
- John C. Kraft
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Jing Li
- Program in Cellular and Molecular Medicine, Children’s Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School
- Viet Q. Le
- Program in Cellular and Molecular Medicine, Children’s Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School
- Rebecca Viazzo Winegar
- Department of Chemistry and Biochemistry, Brigham Young University
- Gerald Maxwell Cherf
- Department of Bioengineering, Stanford University
- Dean Slocum
- Program in Cellular and Molecular Medicine, Children’s Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School
- P. Daniel Poulson
- Department of Chemistry and Biochemistry, Brigham Young University
- Garrett E. Casper
- Department of Chemistry and Biochemistry, Brigham Young University
- Mary L. Vallecillo-Zúniga
- Department of Chemistry and Biochemistry, Brigham Young University
- Jonard Corpuz Valdoz
- Department of Chemistry and Biochemistry, Brigham Young University
- Marcos C. Miranda
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Hua Bai
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Yakov Kipnis
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Audrey Olshefsky
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Tanu Priya
- Department of Materials Science and Engineering, University of Washington
- Lauren Carter
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Rashmi Ravichandran
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Cameron M. Chow
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Max R. Johnson
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Suna Cheng
- Department of Biochemistry and Institute for Protein Design, University of Washington
- McKaela Smith
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Catherine Overed-Sayer
- Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca
- Donna K. Finch
- Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca
- David Lowe
- Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca
- Asim K. Bera
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Gustavo Matute-Bello
- Center for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington
- Timothy P. Birkland
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington
- Frank DiMaio
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Ganesh Raghu
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington
- Jennifer R. Cochran
- Department of Bioengineering, Stanford University
- Lance J. Stewart
- Department of Biochemistry and Institute for Protein Design, University of Washington
- Melody G. Campbell
- Division of Basic Sciences, Fred Hutchinson Cancer Center
- Pam M. Van Ry
- Department of Chemistry and Biochemistry, Brigham Young University
- Timothy Springer
- Program in Cellular and Molecular Medicine, Children’s Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School
- David Baker
- Department of Biochemistry and Institute for Protein Design, University of Washington
- DOI
- https://doi.org/10.1038/s41467-023-41272-z
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 18
Abstract
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.
