Study Reports Design of a Novel and Stable Human Growth Factor

A new study published in the Biophysical Journal has reported development of a stable, biologically active version of the human fibroblast growth factor. Human fibroblast growth factor, or FGF, has potent wound-healing and anti-diabetic properties that could prove useful in the development of new therapeutics.

The novel mechanism by which the researchers were able to enhance the structural stability and cell proliferative activity of FGF has been patent protected.

"FGFs are very important molecules," said Suresh Kumar Thallapuranam, corresponding author on the study and a University Professor of chemistry and biochemistry at the U of A. "In fact, I would say that they are the essence of life. Without FGF, there is no life. From the day we are born as a single cell in our mother's womb, the cells multiply. And for that multiplication, FGF is required."

He added the FGF is not just crucial to the proliferation of cells, but their differentiation into other cells as well. But it's FGF's former role in the proliferation of cells that has researchers eyeing its therapeutic value, potentially playing a role in enhancing the tissue repair process, which is greatly slowed in metabolic diseases like chronic diabetes, leading to infections and even amputations.

The study was more than 10 years in the making, over which time Thallapuranam and his collaborators teased out the three-dimensional structure of human FGF and then unraveled the mechanism by which it binds to heparin and facilitates the signaling of proteins that regulate essential biological processes. In its natural form in the body, human FGF is unstable and has a short biological half-life, likely as an evolutionary hedge against the kind of unchecked cell proliferation that can result in cancer.

The science is complex, but with the help of advanced, multidimensional nuclear magnetic resonance spectroscopy, Thallapuranam and his colleagues were able to manipulate the charges that typically bind FGF to heparin proteins (biomedically, heparin is often used as an anticoagulant). The researchers developed and inserted a charge-reversal mutation, named R126E, into the "heparin binding pocket" that markedly enhanced the structural stability and proliferative activity of FGF. It was the development of this charge-reversing mutation that earned this work a patent protection.

It also laid the foundation for development of what Thallapuranam calls a "super FGF."

While this is beyond the scope of the current paper, Thallapurnam says that super FGF has important metabolic properties, helping cells oxidize fatty acids and glucose and clear cholesterol, which would be beneficial in the treatment of obesity.

The paper was heavily represented by the U of A. Among its 12 coauthors, 10 were from the U of A's Departments of Chemistry and Biochemistry and Biomedical Engineering. They include: Julie Eberle Davis, Rebecca Kerr, Jeevapani J. Hettige, Shivakumar Sonnaila, Shadi A. Badiee, Gayatri Suresh Kumar, Shilpi Agrawal, Srinivas Jayanthi and Mahmoud Moradi.

Thallapuranam's research is supported by grants from the National Institutes of Health. He also serves as director of the Bioenergetics Core of the Arkansas Integrative Metabolic Research Center, where he provides scientific leadership and advanced bioenergetics capabilities to support cutting-edge biomedical research. He holds the Mildred Cooper Chair of Bioinformatics and Biochemistry.