IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-41272-z.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-41272-z
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-41272-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Xianchi Dong & Bo Zhao & Roxana E. Iacob & Jianghai Zhu & Adem C. Koksal & Chafen Lu & John R. Engen & Timothy A. Springer, 2017. "Force interacts with macromolecular structure in activation of TGF-β," Nature, Nature, vol. 542(7639), pages 55-59, February.
    3. Jianchuan Wang & Yang Su & Roxana E. Iacob & John R. Engen & Timothy A. Springer, 2019. "General structural features that regulate integrin affinity revealed by atypical αVβ8," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    4. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    5. Alison E. John & Rebecca H. Graves & K. Tao Pun & Giovanni Vitulli & Ellen J. Forty & Paul F. Mercer & Josie L. Morrell & John W. Barrett & Rebecca F. Rogers & Maryam Hafeji & Lloyd I. Bibby & Elaine , 2020. "Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    6. Nobuyasu Koga & Rie Tatsumi-Koga & Gaohua Liu & Rong Xiao & Thomas B. Acton & Gaetano T. Montelione & David Baker, 2012. "Principles for designing ideal protein structures," Nature, Nature, vol. 491(7423), pages 222-227, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jorge Roel-Touris & Marta Nadal & Enrique Marcos, 2023. "Single-chain dimers from de novo immunoglobulins as robust scaffolds for multiple binding loops," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Zsolt Fazekas & Dóra K. Menyhárd & András Perczel, 2024. "LoCoHD: a metric for comparing local environments of proteins," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Lindsey A. Doyle & Brittany Takushi & Ryan D. Kibler & Lukas F. Milles & Carolina T. Orozco & Jonathan D. Jones & Sophie E. Jackson & Barry L. Stoddard & Philip Bradley, 2023. "De novo design of knotted tandem repeat proteins," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Tamuka M. Chidyausiku & Soraia R. Mendes & Jason C. Klima & Marta Nadal & Ulrich Eckhard & Jorge Roel-Touris & Scott Houliston & Tibisay Guevara & Hugh K. Haddox & Adam Moyer & Cheryl H. Arrowsmith & , 2022. "De novo design of immunoglobulin-like domains," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Ai Vu Hong & Laurence Suel & Eva Petat & Auriane Dubois & Pierre-Romain Le Brun & Nicolas Guerchet & Philippe Veron & Jérôme Poupiot & Isabelle Richard, 2024. "An engineered AAV targeting integrin alpha V beta 6 presents improved myotropism across species," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    6. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative AI," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, National Bureau of Economic Research, Inc.
    7. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    8. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Xiaoke Yang & Mingqi Zhu & Xue Lu & Yuxin Wang & Junyu Xiao, 2024. "Architecture and activation of human muscle phosphorylase kinase," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    10. Efren Garcia-Maldonado & Andrew D. Huber & Sergio C. Chai & Stanley Nithianantham & Yongtao Li & Jing Wu & Shyaron Poudel & Darcie J. Miller & Jayaraman Seetharaman & Taosheng Chen, 2024. "Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    11. Kristy Rochon & Brianna L. Bauer & Nathaniel A. Roethler & Yuli Buckley & Chih-Chia Su & Wei Huang & Rajesh Ramachandran & Maria S. K. Stoll & Edward W. Yu & Derek J. Taylor & Jason A. Mears, 2024. "Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    12. Katherine A. Ray & Joshua D. Lutgens & Ramesh Bista & Jie Zhang & Ronak R. Desai & Melissa Hirsch & Takeshi Miyazawa & Antonio Cordova & Adrian T. Keatinge-Clay, 2024. "Assessing and harnessing updated polyketide synthase modules through combinatorial engineering," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    13. Fan Lu & Liang Zhu & Thomas Bromberger & Jun Yang & Qiannan Yang & Jianmin Liu & Edward F. Plow & Markus Moser & Jun Qin, 2022. "Mechanism of integrin activation by talin and its cooperation with kindlin," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    14. Zengyu Shao & Jiuwei Lu & Nelli Khudaverdyan & Jikui Song, 2024. "Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    15. Yudong Gao & Daichi Shonai & Matthew Trn & Jieqing Zhao & Erik J. Soderblom & S. Alexandra Garcia-Moreno & Charles A. Gersbach & William C. Wetsel & Geraldine Dawson & Dmitry Velmeshev & Yong-hui Jian, 2024. "Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    16. Martin F. Peter & Christian Gebhardt & Rebecca Mächtel & Gabriel G. Moya Muñoz & Janin Glaenzer & Alessandra Narducci & Gavin H. Thomas & Thorben Cordes & Gregor Hagelueken, 2022. "Cross-validation of distance measurements in proteins by PELDOR/DEER and single-molecule FRET," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    17. Jutta Diessl & Jens Berndtsson & Filomena Broeskamp & Lukas Habernig & Verena Kohler & Carmela Vazquez-Calvo & Arpita Nandy & Carlotta Peselj & Sofia Drobysheva & Ludovic Pelosi & F.-Nora Vögtle & Fab, 2022. "Manganese-driven CoQ deficiency," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    18. Alexander Kroll & Sahasra Ranjan & Martin K. M. Engqvist & Martin J. Lercher, 2023. "A general model to predict small molecule substrates of enzymes based on machine and deep learning," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    19. Lisa-Marie Appel & Vedran Franke & Johannes Benedum & Irina Grishkovskaya & Xué Strobl & Anton Polyansky & Gregor Ammann & Sebastian Platzer & Andrea Neudolt & Anna Wunder & Lena Walch & Stefanie Kais, 2023. "The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    20. Maciej K. Kocylowski & Hande Aypek & Wolfgang Bildl & Martin Helmstädter & Philipp Trachte & Bernhard Dumoulin & Sina Wittösch & Lukas Kühne & Ute Aukschun & Carolin Teetzen & Oliver Kretz & Botond Ga, 2022. "A slit-diaphragm-associated protein network for dynamic control of renal filtration," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41272-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.