Cargando…
Rational design of a protein that binds integrin α(v)β(3) outside the ligand binding site
Integrin α(v)β(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 α(v)β(3) outside the classical ligand-binding site. We show ProAgio induces apopt...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895024/ https://www.ncbi.nlm.nih.gov/pubmed/27241473 http://dx.doi.org/10.1038/ncomms11675 |
Sumario: | Integrin α(v)β(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 α(v)β(3) outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin α(v)β(3)-expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin α(v)β(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. |
---|