Kansas State University

MANHATTAN -- A Kansas State University-led team is researching ways to stop the spread of norovirus, a contagious stomach illness that infects one in 15 Americans each year, according to the Centers for Disease Control and Prevention.

Kyeong-Ok Chang, associate professor of diagnostic medicine and pathobiology, is leading researchers as they develop an antiviral drug for market use. The team -- supported by a five-year $5.1 million National Institutes of Health grant -- has identified and is further testing several protease inhibitors with potential for preventing and treating norovirus infection.

Norovirus is the most common form of viral gastroenteritis. It is often called the stomach bug because it causes vomiting and diarrhea for several days. A new Sydney strain of norovirus emerged last year and the Centers for Disease Control and Prevention recently reported that this new strain is now behind 60 percent of norovirus outbreaks.

"You can control infectious diseases by vaccinations, antibiotics for bacterial agents or antiviral drugs for viral agents," said Chang, who has devoted his career to studying noroviruses and rotaviruses, another form of gastroenteritis. "We know that antibiotics and antiviral drugs are a tremendous help to human health. Our goal is to help the patient."

There is currently no vaccine and no antiviral drug to combat norovirus, Chang said. While several organizations are researching vaccine development, Chang's research team is one of the leading groups studying antiviral drugs as a way to treat norovirus.

"The main focus of our research is antiviral drugs because public awareness to norovirus outbreaks is increasing and so is the demand for ways to control norovirus infection," Chang said. "Our team is one of a few groups that have pioneered antiviral drug development in the norovirus field."

Research collaborators at Kansas State University include Duy Hua, a university distinguished professor of chemistry, and Yunjeong Kim, research assistant professor of diagnostic medicine and pathobiology. Other collaborators include William Groutas, a distinguished professor of chemistry at Wichita State University; and Linda Saif, a distinguished professor in the department of veterinary preventive medicine's food animal health research program at Ohio State University.

Each scientist on the team is contributing expertise to the norovirus drug development project. Hua and Groutas are medicinal chemists and are synthesizing compounds specifically designed to bind a virus protein that is essential for virus survival. Chang and Kim are virologists and are testing those compounds in enzyme assays and cell-based assays to determine their effects on the virus. Saif is a virologist and also tests compounds.

"Unlike most bacteria, viruses can only grow in cells," Chang said. "One of the most important ways to tell if a compound is effective against a virus is to test that compound in cell culture to see if it can inhibit the growth of the virus. However, human norovirus does not grow in cells, which has been a great impediment to the development of vaccines and antiviral drugs. That is why we established cell-based assays ourselves. That's our novelty. That's why we initiated this program from Kansas State University and then we looked for collaborators."

In the past few years, the researchers have studied more than 600 compounds and found several compounds with the best potential for drug development. The researchers also are focusing on protease inhibitors, which could prevent viruses from replicating in cells. Other protease inhibitors exist in the market for treating HIV or hepatitis C virus infections.

"Viral proteases are a very good target for antiviral drug development because a virus cannot replicate without its protease," Chang said. "That's why our research has focused on norovirus proteases and protease inhibitors. We know that certain basic structures on our protease inhibitors are effective at inhibiting norovirus, so we continue to generate more compound derivatives based on these basic structures. A compound needs to be effective in enzyme assay and cell-based assay. The compounds also need to have very good pharmacokinetics. We are confident that our compounds can go further than the laboratory."

The scientists also are performing basic virology studies to advance their work further. They are studying how the compounds bind to the virus protease and inhibit protease function using X-ray crystallography and other enzymology tools. In addition, the scientists are investigating other potential targets for developing anti-norovirus drugs, such as host factors to diversify their approaches to norovirus control.

The researchers have filed a patent application for their research. They have published more than 20 papers in the last four years, including articles in the Journal of Virology, the Journal of Medicinal Chemistry, PLOS Pathogens and several other journals.