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Rational design of a protein that binds integrin αvβ3 outside the ligand binding site

Author

Listed:
  • Ravi Chakra Turaga

    (Georgia State University)

  • Lu Yin

    (Georgia State University)

  • Jenny J. Yang

    (Georgia State University)

  • Hsiauwei Lee

    (Georgia State University)

  • Ivaylo Ivanov

    (Georgia State University)

  • Chunli Yan

    (Georgia State University)

  • Hua Yang

    (Eye Center, Emory University)

  • Hans E. Grossniklaus

    (Eye Center, Emory University)

  • Siming Wang

    (Georgia State University)

  • Cheng Ma

    (Georgia State University)

  • Li Sun

    (Center for Diagnostics and Therapeutics, Amoytop Biotech Inc.)

  • Zhi-Ren Liu

    (Georgia State University)

Abstract

Integrin αvβ3 expression is altered in various diseases and has been proposed as a drug target. Here we use a rational design approach to develop a therapeutic protein, which we call ProAgio, that binds to integrin αvβ3 outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin αvβ3-expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin αvβ3. ProAgio also has anti-angiogenic activity and strongly inhibits growth of tumour xenografts, but does not affect the established vasculature. Toxicity analyses demonstrate that ProAgio is not toxic to mice. Our study reports a new integrin-targeting agent with a unique mechanism of action, and provides a template for the development of integrin-targeting therapeutics.

Suggested Citation

  • Ravi Chakra Turaga & Lu Yin & Jenny J. Yang & Hsiauwei Lee & Ivaylo Ivanov & Chunli Yan & Hua Yang & Hans E. Grossniklaus & Siming Wang & Cheng Ma & Li Sun & Zhi-Ren Liu, 2016. "Rational design of a protein that binds integrin αvβ3 outside the ligand binding site," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11675
    DOI: 10.1038/ncomms11675
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