A Virginia Tech researcher has received a $558,747 grant from the National Institute of General Medical Sciences, part of the National Institutes of Health (NIH), to screen small chemical libraries in the Virginia Tech Center for Drug Discovery (VTCDD) to find inhibitors for an enzyme that supports fungal and parasitic infections.
Pablo Sobrado, a professor of biochemistry in the College of Agriculture and Life Sciences and a Fralin Life Science Institute affiliate, studies enzymes that catalyze unique chemical reactions that are essential for microbial survival but are absent in humans.
One of these enzymes, UDP-galactopyranose mutase (UGM), supports infections of some eukaryotic pathogens, such as fungi, parasites, and nematodes that cause many diseases, including invasive aspergillosis, Chagas disease, leishmaniasis, elephantiasis, and river blindness. Despite the significant global suffering and mortality caused by these diseases, there are no effective vaccinations or drug treatments to cure them.
UGM catalyzes the formation of a sugar called galactofuranose. This sugar is a major component of the cell wall in fungi and the cell surface of many parasites and nematodes, so its activity is important for pathogen growth and infection.
“Because of its importance in pathogenesis and its absence in humans, UGM is a target for the development of novel therapeutics against multiple eukaryotic pathogens,” said Sobrado.
Sobrado will conduct this research with John Tanner, a professor of biochemistry at the University of Missouri-Columbia, a co-principal investigator on the grant.
This grant’s research is based on previous NIH-funded work in collaboration with Tanner that led to the discovery of the mechanism and structure of UGM.
“I would not be able to write grants and receive funding without support from the College of Agriculture and Life Science, the Fralin Life Science Institute, and the support of Virginia Tech as a whole. These institutes have provided the VTCDD screening laboratory with the tools and resources to make my grant applications competitive for funding,” said Sobrado.
With the new grant, Sobrado’s team will use the resources at the VTCDD to screen small chemical libraries to find inhibitors for the UGM enzyme.
Sobrado and Tanner’s team will then characterize how the inhibitors work by using biochemical techniques and X-ray crystallography. Ultimately, they will test the effects of these inhibitors on microbial and human cells to make sure the compounds are effective. Once found, these compounds may lead to the development of novel drugs for the treatment of aspergillosis, Chagas disease, leishmaniasis, elephantiasis, and river blindness.
According to the Centers for Disease Control and Prevention:
· The fungus Aspergillus fumigatus causes invasive aspergillosis, a deadly lung infection in immunocompromised individuals, such as leukemia patients and recipients of stem cell or organ transplants. One to two cases of invasive aspergillosis per 100,000 people are reported each year.
· Chagas disease is caused by the parasite Trypanosoma cruzi, which is transmitted to animals and people by insect vectors and is found only in the Americas (mainly, in rural areas of Latin America). More than 300,000 people worldwide are infected with T. cruzi.
· Leishmaniasis is a parasitic disease found in parts of the tropics, subtropics, and southern Europe that can cause skin sores and effect internal organs (usually spleen, liver, and bone marrow). It is caused by infection with Leishmania parasites, which are spread by the bite of phlebotomine sand flies. The incidence rate of leishmaniasis is estimated to be between 1-1.5 million cases a year.
· Elephantiasis or Lymphatic filariasis is a parasitic disease caused by nematodes, which are microscopic, thread-like worms. People with the disease can suffer from disfigurement caused by the swelling of the face and limbs. As a result, the disease is a leading cause of permanent disability worldwide and affects over 120 million people in 73 countries throughout the tropics and sub-tropics of Asia, Africa, the Western Pacific, and parts of the Caribbean and South America.
· River blindness, or onchocerciasis, is caused by the parasitic nematode Onchocerca volvulus in sub-Saharan Africa, the Americas, and the Middle East. It is transmitted through multiple bites by blackflies of the genus Simulium. The disease is called river blindness because the blackfly that transmits the infection lives and breeds near streams and rivers and the infection can result in blindness. In addition to visual impairment or blindness, onchocerciasis can cause skin disease and debilitating itching. About 123 million people globally are at risk for becoming infected with the parasite.
— Written by Kristin Rose