Grant advances drug discovery research against a parasite and a fungus
Pablo Sobrado, assistant professor of biochemistry with the Fralin Life Science Institute at Virginia Tech, has received a $1.5 million grant from the National Institutes of Health (NIH) to advance his research on a unique sugar that occurs both in the cells of the parasite that causes Chagas' disease in millions of people and in the cells of a fungus that causes disease in immuno-compromised individuals.
Sobrado is looking at the biosynthesis of galactofuranose, which is important to these organisms' ability to cause disease, or pathogenesis. The Chagas parasite, Trypasonoma cruzi, is carried primarily by the blood-sucking bug known as vinchuca or “kissing bug.” Galactofuranose allows the parasite to recognize that it has reached its human host and infect human cells, Sobrado said. In the case of the fungus, Aspergillus fumigatus, the sugar is important to cell wall synthesis.
"So the NIH grant funds both vector-borne and infectious disease research, both missions of the Fralin institute," Sobrado said.
Sobrado is studying the enzyme, UDP-galactopyranose mutase (UGM), present in both the parasite and the fungus. UGM is responsible for the biosynthesis of galactofuranose. "When the gene for this enzyme is deleted, both the parasite and the fungus are less virulent. Thus, inhibition of UGM is an attractive target for the development of new chemotherapeutics," said Sobrado.
The work complements another NIH-funded project in Sobrado's lab for the Drug Discovery Consortium for Chagas Disease. "The main focus is to develop a high throughput screening assay to identify compounds that inhibit the enzyme, UGM, which might lead to a new drug," said Sobrado.
The Chagas consortium is led by a group at the University of Georgia. In addition to Virginia Tech, other collaborators are the University of Washington, Northwestern University, and several industries, such as Merck.
On the new NIH award, Sobrado is collaborating with crystallographer John J. Tanner, professor of chemistry at the University of Missouri, Columbia. Tanner is determining the three dimensional structure of the enzyme, while Sobrado is determining the mechanism of action.
Sobrado and colleagues have submitted a paper in the Archives of Biochemistry and Biophysics on their work to date on characterization of unique action of the UGM enzyme. The paper, which was published online by the journal in July and will appear in the journal in October, is.: "Characterization of recombinant UDP-galactopyranose mutase from Aspergillus fumigatus," by Michelle Oppenheimer, Myles B. Poulin, Todd L. Lowary, Richard F. Helm, and Sobrado. Oppenheimer of Charlotte, N.C., is a Ph.D. student in biochemistry in the College of Agriculture and Life Sciences at Virginia Tech, who has a two year Fellowship from the American Heart Association to advance her research the parasite that causes Chagas' disease, which can lead to swelling and inflammation of the heart. Helm is associate professor of biochemistry at Virginia Tech. Poulin and Lowary are from the Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, University of Alberta.
The NIH award is a five-year research project (RO1) grant. R01 grants provide support for health-related research and development based on the mission of the NIH.
The Fralin Life Science Institute is a member of the Research Institutes of Virginia Tech. The Research Institutes of Virginia Tech enhance the university's ability to address large scale research opportunities by crossing traditional disciplinary and college lines. The six institutes provide clients access to world class expertise across many disciplines and to the scientific and technical capability of specially equipped, advanced laboratories.