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De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8

Author

Listed:
  • Anindya Roy

    (University of Washington)

  • Lei Shi

    (University of Washington
    Encodia Inc, 5785 Oberlin Drive)

  • Ashley Chang

    (Brigham Young University)

  • Xianchi Dong

    (Harvard Medical School
    Nanjing University
    Ministry of Education)

  • Andres Fernandez

    (Fred Hutchinson Cancer Center)

  • John C. Kraft

    (University of Washington)

  • Jing Li

    (Harvard Medical School)

  • Viet Q. Le

    (Harvard Medical School)

  • Rebecca Viazzo Winegar

    (Brigham Young University)

  • Gerald Maxwell Cherf

    (Stanford University
    Denali Therapeutics)

  • Dean Slocum

    (Harvard Medical School)

  • P. Daniel Poulson

    (Brigham Young University)

  • Garrett E. Casper

    (Brigham Young University)

  • Mary L. Vallecillo-Zúniga

    (Brigham Young University)

  • Jonard Corpuz Valdoz

    (Brigham Young University)

  • Marcos C. Miranda

    (University of Washington
    Karolinska Institutet and Karolinska University Hospital)

  • Hua Bai

    (University of Washington)

  • Yakov Kipnis

    (University of Washington
    University of Washington)

  • Audrey Olshefsky

    (University of Washington
    University of Washington)

  • Tanu Priya

    (University of Washington
    Northwestern University Feinberg School of Medicine)

  • Lauren Carter

    (University of Washington)

  • Rashmi Ravichandran

    (University of Washington)

  • Cameron M. Chow

    (University of Washington)

  • Max R. Johnson

    (University of Washington)

  • Suna Cheng

    (University of Washington)

  • McKaela Smith

    (University of Washington)

  • Catherine Overed-Sayer

    (BioPharmaceuticals R&D, AstraZeneca
    BioPharmaceuticals R&D, AstraZeneca)

  • Donna K. Finch

    (BioPharmaceuticals R&D, AstraZeneca
    Alchemab Therapeutics Ltd)

  • David Lowe

    (BioPharmaceuticals R&D, AstraZeneca
    Robert Robinson Avenue)

  • Asim K. Bera

    (University of Washington)

  • Gustavo Matute-Bello

    (University of Washington)

  • Timothy P. Birkland

    (University of Washington)

  • Frank DiMaio

    (University of Washington)

  • Ganesh Raghu

    (University of Washington
    University of Washington)

  • Jennifer R. Cochran

    (Stanford University)

  • Lance J. Stewart

    (University of Washington)

  • Melody G. Campbell

    (Fred Hutchinson Cancer Center)

  • Pam M. Ry

    (Brigham Young University)

  • Timothy Springer

    (Harvard Medical School)

  • David Baker

    (University of Washington
    University of Washington)

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.

Suggested Citation

  • 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 & Garret, 2023. "De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41272-z
    DOI: 10.1038/s41467-023-41272-z
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    References listed on IDEAS

    as
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