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

DOI
https://doi.org/10.1038/s41467-023-41272-z
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 18

Abstract

Read online

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.