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

Roy, Anindya; Shi, Lei; Chang, Ashley; Dong, Xianchi; Fernandez, Andres; Kraft, John C.; Li, Jing; Le, Viet Q.; Winegar, Rebecca Viazzo; Cherf, Gerald Maxwell; Slocum, Dean; Poulson, P. Daniel; Casper, Garrett E.; Vallecillo-Zúniga, Mary L.; Valdoz, Jonard Corpuz; Miranda, Marcos C.; Bai, Hua; Kipnis, Yakov; Olshefsky, Audrey; Priya, Tanu; Carter, Lauren; Ravichandran, Rashmi; Chow, Cameron M.; Johnson, Max R.; Cheng, Suna; Smith, McKaela; Overed-Sayer, Catherine; Finch, Donna K.; Lowe, David; Bera, Asim K.; Matute-Bello, Gustavo; Birkland, Timothy P.; DiMaio, Frank; Raghu, Ganesh; Cochran, Jennifer R.; Stewart, Lance J.; Campbell, Melody G.; Ry, Pam M.; Springer, Timothy; Baker, David

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. Ry (), Timothy Springer () and David Baker ()
Additional contact information
Anindya Roy: University of Washington
Lei Shi: University of Washington
Ashley Chang: Brigham Young University
Xianchi Dong: Harvard Medical School
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
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
Hua Bai: University of Washington
Yakov Kipnis: University of Washington
Audrey Olshefsky: University of Washington
Tanu Priya: University of Washington
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
Donna K. Finch: BioPharmaceuticals R&D, AstraZeneca
David Lowe: BioPharmaceuticals R&D, AstraZeneca
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
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

Nature Communications, 2023, vol. 14, issue 1, 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.

Date: 2023
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DOI: 10.1038/s41467-023-41272-z

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