Engineered protein cuts inflammation and blood vessel formation in chronic diseases

ProAgio
ProAgio (green) binding to integrin v3--Screenshot courtesy of Georgia State University

Georgia State University researchers have designed a protein which they say can efficiently target an important cell surface receptor implicated in many diseases. The findings could lead to new treatments for a panel of chronic diseases, including cancers.

Zhi-Ren Lui and his team at the Department of Biology at Georgia State published their work in the journal Nature Communications.

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The scientists engineered a synthetic protein, which they named ProAgio, using a naturally occurring human protein as the scaffold. It is designed to target an integrin v3 receptor which is a known drug target for the development and progression of many diseases including skin fibrosis, rheumatoid arthritis and metastatic cancer.

"This integrin pair, v3, is not expressed in high levels in normal tissue," said Liu, referring to the clear benefit of a drug that doesn’t interfere with healthy cells. "In most cases, it's associated with a number of different pathological conditions. Therefore, it constitutes a very good target for multiple disease treatment."

Integrins are receptors found on the cell surface that bind to the extracellular matrix, anchoring the cell in its cellular environment. Integrin v3 is a protein made from a pair of subunits, it has been previously targeted in the hope of reduce inflammation and the number of new blood vessels--in the case of the above mentioned disease where both processes have gone haywire.

Other groups have targeted the ligand binding domain of integrin v3 with limited success. "We took a unique angle," Lui said. "We designed a protein that binds to a different site. Once the protein binds to the site, it directly triggers cell death. When we're able to kill pathological cells, then we're able to kill the disease." ProAgio targets a new binding site on the integrin v3 receptor found in the cytoplasmic fraction of the protein.

ProAgio binds sufficiently with integrin v3 and importantly is shown to recruit caspase 8,  a protein that initiates apoptotic cell death. This ensures that the cells expressing integrin v3 at an abnormal rate are killed off and inflammation is lowered as a consequence.

So far, the team has shown promise in a mouse model of cancer with ProAgio outperforming other agents that bind to the well characterized ligand domain. They found tumor growth was halted and the number of new blood vessels supplying the tumor were reduced.

In addition, they didn’t observe any toxicity to normal tissue and existing blood vessels in healthy tissue were left unaltered.

- here’s the release

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