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Author Notes:

Correspondence and requests for materials should be addressed to Z.-R.L. (email: zliu8@gsu.edu).

R.C.T. and L.Y. contributed equally to this work.

A full list of author contributions appears at the end of the article.

We thank Drs Liangwei Li, Vaishali Pannu and Mr Yinwei Zhang for their critical comments. We are grateful to Ms. Birgit Neuhaus for her assistance in microscopic imaging.

Z.-R.L. holds shares in the company ProDa BioTech LLC, which licensed the rights to commercialize ProAgio. L.S. holds shares in the company Amoytop Biotech Co. Ltd, which licensed the rights to commercialize ProAgio in China. The remaining authors declare no competing financial interests.

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Research Funding:

This work is supported in part by research grants from National Institute of Health (CA175112, CA118113) and Georgia Cancer Coalition to Z.-R.L.

Researches in Dr Jenny Yang’s laboratory is supported by National Institute of Health (EB007268, HL042220), in Grossniklaus’s laboratory is supported by National Institute of Health (EY06306) and Research to Prevent Blindness, Inc. (New York, NY), and in Dr Ivaylo Ivanov’s laboratory is supported by National Science Foundation (NSF, CAREER 1149521 and National Institutes of Health grant (GM110387)).

Mr. R.C.T. is supported by a MBD fellowship, GSU.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • CELL-ADHESION MOLECULE
  • HUMAN BREAST-CANCER
  • ALPHA-V-BETA-3 INTEGRIN
  • THERAPEUTIC TARGETS
  • CRYSTAL-STRUCTURE
  • EXPRESSION
  • ANGIOGENESIS
  • METASTASIS
  • ACTIVATION

Rational design of a protein that binds integrin α(v)β(3) outside the ligand binding site

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Journal Title:

Nature Communications

Volume:

Volume 7

Publisher:

, Pages 11675-11675

Type of Work:

Article | Final Publisher PDF

Abstract:

Integrin αν β3 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 αν β3 outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin αν β3 -expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin αν β3. 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.

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© 2016, Rights Managed by Nature Publishing Group

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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