Kansas State University

MANHATTAN -- If cats really had nine lives, one reason might be to help deal with the wide variety of diseases that threaten feline health.

Yunjeong Kim, a research assistant professor in the College of Veterinary Medicine at Kansas State University, has developed a research approach that tackles two deadly infectious feline diseases at the same time. Her work is being supported by a $156,342 award from the Morris Animal Foundation.

"Coronavirus and calicivirus infections are very common among cats, and cats tend to get repeatedly infected by these viruses throughout their lifetime," said Kim, who works in the college's diagnostic medicine and pathobiology department. "Feline coronavirus can cause gastroenteritis, and calicivirus often causes ulcerative upper respiratory infection with gingivitis and stomatitis. In most cases, these viral infections are mild and self-limited."

But Kim says some cats that are infected with these viruses develop life-threatening illnesses with high fatality. The deadly form of feline coronavirus infection, feline infectious peritonitis, or FIP, has been recognized since the early 1970s and is currently the leading infectious cause of death in young cats. More recently, virulent systemic feline calicivirus infection, or vs-FCV, has emerged associated with a systemic infection that is frequently fatal. Since 1998, numerous outbreaks of vs-FCV infection have been reported in animal shelters and catteries with mortality as high as 67 percent.

Vaccines are available for FIP and vs-FCV, but their field application seems to be limited or not recommended due to various reasons, and there is no antiviral drug for these viral infections. That means there is a great need for safe and effective antiviral drugs for these diseases.

"We have been working on a virus protease that is highly conserved among some viruses, including coronavirus and calicivirus," Kim said. "This virus protease, 3C-like protease, is essential for successful virus replication, thus it is a promising target for antiviral drug development."

Kim is collaborating with Kansas State University's Kyeong-Ok Chang, a virologist in the diagnostic medicine and pathobiology department, and with Duy Hua and William Groutas, who are medicinal chemists at Kansas State University and Wichita State University, respectively.

"We designed a series of inhibitors for 3C-like protease, and identified a couple of promising compounds through various steps involving exploring the relationship between a compound structure and its biological activity," Kim said. "Some of the work has been supported by another grant from the Winn Feline Foundation. The compounds effective against FIP virus are currently under investigation for pharmacokinetic properties in cats in collaboration with Dr. Niels C. Pedersen at the University of California, Davis. This will give us valuable information that will guide our further efforts in moving forward with development of a safe and efficacious antiviral drug for FIP."

Kim continues to probe the possibility of developing antiviral compounds that are active against both FIPV and vs-FCV. The drug discovery and development process is very long and expensive, and can be fraught with difficulties.

"More and more focus has been placed on the development of broad-spectrum antiviral drugs that work against multiple viruses," Kim said. "That is the reason we also generated a series of compounds with broad activity against FIP and vs-FCV based on the structural and functional similarities of the proteases of these viruses. For the next three years, supported by the Morris Animal Foundation grant, we will characterize those compounds for drug-like properties and also identify additional backup compounds. In addition to protease inhibitors, we identified a cellular enzyme that is important in both FIPV and FCV. The grant also will support our research on the roles of the cellular enzyme in virus replication, which may provide important insight into the pathogenicity of these viruses and also may lead to a new antiviral drug target."

The challenge, according to Kim, is that an antiviral drug must not only be effective at reducing clinical symptoms and mortality, but it also must be safe and, preferably, available orally.

"We are currently at an early stage and there will be many obstacles to overcome," she said. "But we are encouraged by the progress we are making toward the goal."