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Rational design of a protein that binds integrin ?v?3 outside the ligand binding site.

ABSTRACT: Integrin ?v?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 ?v?3 outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin ?v?3-expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin ?v?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.

SUBMITTER: Turaga RC

PROVIDER: S-EPMC4895024 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Turaga Ravi Chakra RC Yin Lu L Yang Jenny J JJ Lee Hsiauwei H Ivanov Ivaylo I Yan Chunli C Yang Hua H Grossniklaus Hans E HE Wang Siming S Ma Cheng C Sun Li L Liu Zhi-Ren ZR

Nature communications 20160531

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 xenog ...[more]

PMID: 27241473

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