Researchers at Georgia State
University have designed a protein that can effectively target a cell surface
receptor linked to a number of diseases, including cancer. The researchers
believe this synthetic protein, which they named ProAgio, has the potential to
be a therapeutic treatment for various illnesses. Their work was recently published in Nature Communications.
The team created ProAgio from a
human protein to target the cell surface receptor integrin aVß3. This receptor
is expressed in a variety of cells, including new blood vessels, activated
macrophages, metastasizing cancer cells and bone cells critical to maintenance
and repair. Its abnormal expression is linked to the development and progression
of a number of diseases, which makes it a drug development focus. In
particular, integrin aVß3 is seen as a potential target for preventing inflammation and the
growth of new blood vessels.
As lead author Zhi-Ren Liu, a professor
in the department of biology at Georgia State, said in a press release, “This integrin pair, aVß3, is not expressed in high levels
in normal tissue. In most cases, it’s associated with a number of different
pathological conditions. Therefore, it constitutes a very good target for
multiple disease treatment.”
Previous approaches to targeting
this integrin have focused on ligand binding, or attaching a molecule to the
active site. However, this strategy has not proven effective yet. The Georgia
State University researchers instead created ProAgio to target the integrin at
a unique site. The team found ProAgio induces apoptosis, or programmed cell
death, of cells that express integrin aVß3. The protein works by recruiting caspase 8, an
enzyme that plays an essential role in programmed cell death, to the
cytoplasmic area of integrin aVß3.
Lui continued, “We took a
unique angle. 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.”
Researchers in this study
conducted various cell and molecular testing to confirm ProAgio interacts and
binds well with integrin aVß3. Mouse model cancer tests showed ProAgio strongly inhibits tumor
growth. Tissue analyses indicated the protein effectively prevents the growth
of tumor blood vessels, while existing blood vessels were not affected.
Toxicity tests also showed that ProAgio is not toxic to normal tissue and
organs in mice. Finally, ProAgio was much more effective in inducing cell death
than other agents tested.