Researchers, including one of Indian-origin, have designed a new protein that can effectively kill cells linked to the development and progression of cancer and a number of other diseases.
ProAgio, which is created from a human protein, targets the cell surface receptor integrin v3 at a novel site that has not been targeted by other scientists.
The researchers from Georgia State University in the US found ProAgio induces apoptosis, or programmed cell death, of cells that express integrin v3.
This integrin has been a focus for drug development because abnormal expression of v3 is linked to the development and progression of a number of diseases.
“This integrin pair, v3, is not expressed in high levels in normal tissue,” said Zhi-Ren Liu, lead author of the study and professor at Georgia State.
“In most cases, it’s associated with a number of different pathological conditions. Therefore, it constitutes a very good target for multiple disease treatment,” said Liu.
Integrins are cell surface receptors that play a critical role in cells that attach to the extracellular matrix.
They are composed of different combinations and subunits. Different types of cells have different pairs of subunits.
Integrin v3 has been studied by many scientists as a potential target for drugs that prevent inflammation and the growth of new blood vessels.
This integrin is expressed in the cells of new blood vessels, activated macrophages (immune cells that are involved in the first defence against infection), some cancer cells that metastasise or spread to other parts of the body and bone cells that are critical to maintenance and repair.
Previous approaches to targeting this integrin have focused on ligand binding, or attaching a molecule to the active site, which has not been effective.
There is an urgent need to develop agents that target this integrin at sites other than the ligand-binding site, Liu 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,” Lui said.
Researchers, including Ravi Turaga of Georgia State, performed extensive cell and molecular testing that confirmed ProAgio interacts and binds well with integrin v3.
They found ProAgio induces apoptosis by recruiting caspase 8, an enzyme that plays an essential role in programmed cell death, to the cytoplasmic area of integrin v3.
ProAgio was much more effective in inducing cell death than other agents tested.
In addition, tests with mouse models of cancer showed ProAgio strongly inhibits tumour growth. Tissue analyses indicated the protein effectively prevents the growth of tumour blood vessels, while existing blood vessels were not affected.
The findings were published in the journal Nature Communications.