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

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 and Zhi-Ren Liu ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11675

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