Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms11675
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Funding
- National Institute of Health [CA175112, CA118113, EB007268, HL042220, EY06306, GM110387]
- Georgia Cancer Coalition
- Research to Prevent Blindness, Inc. (New York, NY)
- National Science Foundation (NSF) [CAREER 1149521]
- MBD fellowship, GSU
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1149521] Funding Source: National Science Foundation
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Integrin alpha(v)beta(3) 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 alpha(v)beta(3) outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin alpha(v)beta(3)-expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin alpha(v)beta(3). 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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