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

• Type of Material: Article
• Authors: 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, Emory University; Hans Grossniklaus, Emory University; Siming Wang, Georgia State University; Cheng Ma, Georgia State University; Li Sun, Amoytop Biotech Inc; Zhi-Ren Liu, Georgia State University
• Language: English
• Date: 2016-05-01
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2016, Rights Managed by Nature Publishing Group
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms11675
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 7
• Start Page: 11675
• End Page: 11675
• Grant/Funding Information: 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.; This work is supported in part by research grants from National Institute of Health (CA175112, CA118113) and Georgia Cancer Coalition to Z.-R.L.
• Keywords: THERAPEUTIC TARGETS; CRYSTAL-STRUCTURE; Science & Technology; ACTIVATION; Science & Technology - Other Topics; ANGIOGENESIS; Multidisciplinary Sciences; HUMAN BREAST-CANCER; ALPHA-V-BETA-3 INTEGRIN; CELL-ADHESION MOLECULE; EXPRESSION; METASTASIS
• Research Categories: Chemistry, Pharmaceutical; Health Sciences, Pharmacology; Chemistry, Biochemistry

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.