Over the past decade, the laboratory has responded to national emergencies, studying highly infectious diseases such as SARS and others. Today it is being called upon in research efforts focusing on the novel coronavirus, SARS-CoV-2, and the disease it causes, COVID-19. And in that lab, researchers are exploring compounds that hold promise as therapeutic agents against the disease and could be grown quickly in host tobacco plants.

That’s right, tobacco. A strain of the reviled plant that has caused fatal diseases for centuries could be the key to quickly mass-producing a preventive agent, treatment or vaccine for COVID-19.

“A protein in the university’s own proprietary portfolio and other compounds from industry sources may be useful against SARS-CoV-2,” said Kenneth Palmer, PhD, director of ±«´Ç´Úł˘â€™s (CPM).Ěý “We are currently conducting laboratory research with these compounds that could eventually lead to a therapeutic agent against COVID-19.”

±«´Ç´Úł˘â€™s (RBL) is housed in the CPM and is part of a network of 12 regional and two national labs that were established with support from the NIH to conduct research with infectious agents. The national labs are located at Boston University and at the University of Texas Medical Branch at Galveston. Regional labs are located at the University of Chicago, Duke University, Boston University and other universities throughout the U.S. The RBL network stands ready in response to public health emergencies and emerging diseases such as the novel coronavirus.

The UofL RBL includes Biosafety Level 3 facilities built to the most exacting federal safety and security standards. The stringently secure facilities protect researchers and the public from exposure to the pathogens being investigated. As part of the RBL network, the UofL RBL is able to respond to needs of researchers, federal agencies and pharmaceutical companies nationwide to conduct research with infectious agents.

Palmer and his research team received samples of SARS-CoV-2 last month and are researching it only in the highly secure confines of the RBL. Covered head to toe in personal protective equipment to prevent self-infection, the researchers now are testing the therapeutic candidates against the disease in cell cultures.

The UofL compound is known as and is co-owned by the university with the National Cancer Institute and the University of Pittsburgh. It is a potent anti-viral protein that possesses microbicidal capabilities. The other compounds are proprietary to their respective companies.

The research goal is to identify the best potential treatment option that could eventually be tested in humans, first at UofL to gauge its safety and efficacy and then later at the University of Pittsburgh and other clinical trial sites to continue to test its effectiveness. Although there are no guarantees, “we believe we could move into human clinical trials by the end of the year,” Palmer said.

That’s where the tobacco plants come in. A large amount of the ultimate therapeutic will be needed for human trials. Kentucky’s historical cash crop is a perfect host to produce the quantities needed.

“The unique quality about studying these compounds in Kentucky is that we can rapidly scale up production of tobacco plants to produce the large amounts of the agent we will need for human testing,” Palmer said. “As people already know, tobacco grows very well in Kentucky.”

Some of the compounds are already showing promise in the laboratory. While the end of the year seems far off in the current coronavirus climate, it is realistic because “SARS-CoV-2 may be with us for a couple of winter seasons. We’d like to have a product that could be tested if the infection comes back in the cold season like influenza does,” Palmer said.

If it does, Palmer and his team will be ready. “We think we will be able to deliver the drug as a nasal spray and hope we can use it as a preventive, pre-exposure treatment before a vaccine could be developed. This will be important for the public and especially for those who are at risk because of their age or pre-existing health conditions or because they work in health care.”

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The center, headquartered at the University of Tennessee Health Science Center in Memphis, will develop therapeutic drugs to treat three mosquito-borne alphaviruses that cause serious illness in humans and horses: Venezuelan equine encephalitis virus (VEEV), Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV). Although a vaccine is available for horses, there are no FDA-approved treatments or preventive vaccines for these viruses in humans.

Chung, an associate professor in the and Department of Microbiology & Immunology at UofL, said the center’s goal is to refine potent small molecule compounds the researchers previously identified as promising as antiviral drugs for treating the encephalitis viruses, and enable those compounds to move to the next step of research, clinical trials in humans.

“In my previous research I found that these compounds inhibit the viral replication cycle. However, we want to further understand which target molecules are interacting with the compound,” Chung said. He described the mechanism of the compounds the group is investigating as similar to the way the drug nevirapine, a non-nucleoside reverse transcriptase inhibitor, works in treating human immunodeficiency virus (HIV).

“This project is to develop a new antiviral compound to treat these diseases in humans,” Chung said. “However, we do not limit our applications of this drug to only humans, as it may be possible to adapt it for treating horses as well.”

These equine encephalitis viruses infect humans and horses through the bite of an infected mosquito. According to the Centers for Disease Control and Prevention, symptoms of infection include fever, chills, headache and vomiting. Outbreaks of the Western and Venezuelan viruses are uncommon, and an average of only seven human cases of have been reported annually in the United States throughout the past ten years. However, the disease may leave people with permanent neurological symptoms, and approximately 30% of people who contract the Eastern equine encephalitis virus will die from the disease.

According to Chung, the potential for the viruses to be used in bioterrorism is perhaps even more worrisome. The CDC recognizes viral encephalitis as a Category B human biothreat, making the development of a treatment important.

Chung’s co-principal investigators in the center are Colleen Jonsson, PhD, of the University of Tennessee Health Science Center who directs the center, and Jennifer E. Golden, PhD, of the University of Wisconsin-Madison School of Pharmacy.

“The goal of our new Center of Excellence is to further develop novel therapeutic molecules discovered by our team that are highly potent across all three viruses, moving the optimal ones forward into pre-clinical development,” said Jonsson, formerly director of the UofL Center for Predictive Medicine.

Chung will test the compounds for toxicity against human cells in vitro, deciphering their molecular mechanisms and determining their resistance threshold utilizing the facilities and staff at the at UofL. He also will test the compounds’ resistance threshold that inevitably develops over time, along with Juw Won Park, PhD, assistant professor of computer engineering in the at UofL.

Once their work is completed, the researchers expect the new drugs would be ready to begin clinical trial testing in humans.

Researchers at the University of Louisville  are working at the forefront in combating these pathogens. The CPM has been testing the effectiveness of new drugs against P. aeruginosa under a contract with the National Institutes of Health since 2013, and a new contract from the U.S. Food and Drug Administration will expand the center’s work in testing new drugs against this pathogen. Under the new two-year, $933,606 contract, CPM will develop a validated model for screening antimicrobial drugs against P. aeruginosa.

“This model likely will play an important role in drug development pipelines leading to identification of new antimicrobial drugs,” said Matthew Lawrenz, PhD, associate professor of microbiology and immunology who is leading the research. “Researchers at UofL and from around the world will use the model to screen new antimicrobials against multi-drug resistant bacteria prior to clinical trials.”

Forest Arnold, DO, hospital epidemiologist for UofL Hospital and associate professor in the Division of Infectious Diseases in the UofL School of Medicine, said multi-drug resistant bacteria and XDR bacteria, those with resistance to all existing antibiotics, are evolving faster than the drugs to kill them.

“The germs get smarter as we make new drugs. If we are going to stay on top of them, we need new antibiotics, especially new classes of antibiotics — those with a new mechanism of action that the germ hasn’t seen before,” Arnold said.

Infections with MDR bacteria are particularly threatening for patients with weakened immune systems, those who have had multiple rounds of treatment with antibiotics, and in patients using devices such as ventilators and blood catheters. Since these bacteria are now resistant to many of the antibiotic drugs used to treat them, they can lead to severe infections and death.

“If you have an infection with a bacterium we don’t have an antibiotic to treat, it could kill you,” Arnold said.

P. aeruginosa is common in the environment and in otherwise healthy people, it may cause relatively minor of the ear, skin or eye. However, in people with weakened immune systems or in hospital settings, P. aeruginosa can cause serious, life-threatening infections of the blood, lungs, digestive tract or tissue. Infected wounds will have a green pus or discharge and a fruity smell.

The validated animal model, to be developed by UofL researchers with collaborators at the University of Kentucky and the University of Wisconsin, will be used to test new compounds developed by drug companies and research labs around the world against P. aeruginosa. This model will allow testing against multiple strains of pseudomonas and will give more detailed information about the effectiveness of the drugs being tested.

“The previous methods we used for testing the drugs provided basic information about a compound’s effectiveness. This new model will allow us to test anything from older classes of antibiotics to brand new classes and will provide information on dosing and scheduling. In addition, we will be able to test different strategies, such as immunomodulation – targeting the host to better respond to the infection as opposed to directly killing the bacteria,” Lawrenz said.

The CPM’s new contract with the FDA will take advantage of the sophisticated resources at the , located on the UofL ShelbyHurst Campus, which provide the environment necessary for this work.

“This new contract from the Food and Drug Administration supports the development of a model for understanding how bacteria build resistance to current commercially available antibiotics, which in turn, will lead to the discovery of new drugs or methods to combat a variety of infectious diseases,” said Robert Keynton, PhD, interim executive vice president for research and innovation at UofL. “The UofL Center for Predictive Medicine and the Regional Biocontainment Laboratory represents a significant investment in infrastructure, faculty and staff by the university in the field of emerging infectious diseases, which is one of our research and training strategic priorities.”