ArticleNature communications2023
De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8.
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Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35citing papers in PubMed
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35 citing papers in PubMed.
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- Conformational Preference Classification of Integrin-Binding Ligands Using Free Energy Perturbation.JACS Au · 2026Article
- The potential and therapeutic advances of the integrin family in neurological disorders.Neural regeneration research · 2026Article
- De novo design of miniproteins targeting GPCRs.Nature · 2026Article
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- Tools For Building Artificial Biological Nanostructures.ACS nano · 2026Review
- Structural basis for the differential recognition of integrin αvβ3 by rhodostomin and trimucrin.Communications biology · 2026Article
- The emerging role of integrin signaling in pulmonary vascular disease.American journal of physiology. Lung cellular and molecular physiology · 2026Review
- Inflammation drives TGFβ1 activation via the αvβ6 integrin-mechanotransduction pathway in human skin.iScience · 2026Article
- AI-Driven Design of Miniproteins as Potential Allosteric Modulators.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Phagocytic clearance of targeted cells with a synthetic ligand.Nature biomedical engineering · 2026Article
- De novo protein design: a transformative frontier in clinical protein applications.Journal of translational medicine · 2026Review
- AI-Driven De Novo Binder Design: From Structure Prediction to Closed-Loop Optimization.Computational and structural biotechnology journal · 2026Review
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- Design of minibinder proteins as universal antagonists against canine and human TNFα.Communications biology · 2025Article
- De Novo Design of Miniprotein Inhibitors of Bacterial Adhesins.Research square · 2025Article
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- Antifibrotic Efficacy of a Nintedanib-Peptide Conjugate and Diagnostic Potential of a Fluorescent Companion Probe Targeting αACS pharmacology & translational science · 2025Article
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Authors and funding
40 authors.
Anindya Roy *Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
Lei Shi *Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
Ashley Chang *Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA.
Xianchi DongProgram in Cellular and Molecular Medicine, Children's Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School, Boston, MA, USA.
Andres FernandezDivision of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.ORCID http://orcid.org/0000-0001-8006-1724
John C KraftDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.ORCID http://orcid.org/0000-0002-7931-7478
Jing LiProgram in Cellular and Molecular Medicine, Children's Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School, Boston, MA, USA.
Viet Q LeProgram in Cellular and Molecular Medicine, Children's Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-2417-8642
Rebecca Viazzo WinegarDepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA.
Gerald Maxwell CherfDepartment of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
Dean SlocumProgram in Cellular and Molecular Medicine, Children's Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School, Boston, MA, USA.
P Daniel PoulsonDepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA.ORCID http://orcid.org/0000-0002-1471-1378
Garrett E CasperDepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA.
Mary L Vallecillo-ZúnigaDepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA.ORCID http://orcid.org/0000-0001-7662-4010
Jonard Corpuz ValdozDepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA.ORCID http://orcid.org/0000-0002-7106-1009
Marcos C MirandaDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.ORCID http://orcid.org/0000-0002-2839-6997
Hua BaiDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
Yakov KipnisDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.ORCID http://orcid.org/0000-0002-3057-4916
Audrey OlshefskyDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.ORCID http://orcid.org/0000-0002-4028-5587
Tanu PriyaDepartment of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.
Lauren CarterDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
Rashmi RavichandranDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
Cameron M ChowDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
Max R JohnsonDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
Suna ChengDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
McKaela SmithDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
Catherine Overed-SayerResearch and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Donna K FinchResearch and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
David LoweResearch and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Asim K BeraDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.ORCID http://orcid.org/0000-0001-9473-2912
Gustavo Matute-BelloCenter for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, USA.
Timothy P BirklandDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
Frank DiMaioDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
Ganesh RaghuDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
Jennifer R CochranDepartment of Bioengineering, Stanford University, Stanford, CA, 94305, USA.ORCID http://orcid.org/0000-0002-6532-9873
Lance J StewartDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
Melody G CampbellDivision of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA. melody@fredhutch.org.ORCID http://orcid.org/0000-0003-1909-5751
Pam M Van RyDepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA. pvanry@byu.edu.
Timothy SpringerProgram in Cellular and Molecular Medicine, Children's Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School, Boston, MA, USA. springer@crystal.harvard.edu.ORCID http://orcid.org/0000-0001-6627-2904
David BakerDepartment of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA. dabaker@uw.edu.ORCID http://orcid.org/0000-0001-7896-6217
Funding
Translational Bioimaging Core Shared ResourceP30CA015704 · NCI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI Eric Collisson · 1985 to 2026
$296.4MTRAINING IN MOLECULAR BIOPHYSICST32GM008268 · NIGMS · UNIVERSITY OF WASHINGTON · PI KOLLMAN, JUSTIN M, ZHENG, NING · 1988 to 2023
$8.6MHigh resolution structure modeling with RosettaR01GM092802 · NIGMS · UNIVERSITY OF WASHINGTON · PI BAKER, DAVID · 2010 to 2017
$2.3MThe Molecular Basis for Integrin-Mediated Bidirectional SignalingR35GM147414 · NIGMS · FRED HUTCHINSON CANCER CENTER · PI Melody G Campbell · 2022 to 2026
$2.2MTGF-beta latency and activationR01AR067288 · NIAMS · BOSTON CHILDREN'S HOSPITAL · PI SPRINGER, TIMOTHY A · 2015 to 2019
$1.9MBlocking Latent TGF-β2 Activation as a Therapeutic Strategy for Renal FibrosisK01DK124443 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI LE, VIET QUOC · 2021 to 2025
$771kNCI NIH HHS P30 CA015704NIAMS NIH HHS R01 AR067288NIDDK NIH HHS K01 DK124443NIGMS NIH HHS R01 GM092802NIGMS NIH HHS R35 GM147414NIGMS NIH HHS T32 GM008268
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.
Indexed as
IntegrinsPulmonary FibrosisAnimalsCell MembraneCryoelectron MicroscopyDisease Models, AnimalMiceIntegrins
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