A lasting collaboration between Penn Vet’s Freedman (seated) and Harty is giving rise to promising compounds for targeting Ebola. The pair’s company, Intervir, is now working to refine inhibitor molecules they hope will prove effective at quelling Ebola infections
in animal models—and one day, humans.
Ebola just isn’t going away. Following the major 2014 outbreak in West Africa, the deadly infection came back with a vengeance last year in the Democratic Republic of Congo, where the death toll recently reached 2,000. Since long before the earlier outbreak raised Americans’ consciousness about the disease, researchers Ronald Harty and Bruce Freedman of the School of Veterinary Medicine had been collaborating with other scientists to find drugs to dispatch the infection.
Like many viruses, Ebola can mutate quickly, potentially evading the reach of some targeted therapies. The disease can also claim lives in short order. Those who don’t survive their infection can die within days. And while a vaccine for the virus exists, it’s not widely distributed. For these reasons, Harty and Freedman and colleagues have aimed their scientific investigations at developing an inhibitor compound that interferes with the interaction between the virus and host it’s attempting to overwhelm.
A virus such as Ebola spreads by hijacking a host cell’s machinery, as it lacks its own equipment to carry out tasks critical to its ability to reproduce. Blocking the virus’s ability to interact with host proteins is a strategy to limit infection. For Harty and Freedman, a specific target has been blocking budding, a process by which the virus slips out of a host cell after replicating itself inside.
“The idea behind the host approach is, not only should it work against quickly evolving strains of the virus, because these interacting domains are critical to the viruses’ life cycle,” says Freedman, “but also viruses often use similar mechanisms to interact with the host. So, much like using a broad-spectrum antibiotic to treat a bacterial infection, by using a drug that targets the host-viral interaction you may be able to block a half dozen or more different pathogens that could be using those same mechanisms.”
At Penn Vet, researchers use a variety of laboratory tests that don’t involve the actual viruses to screen compounds that might block budding and slow down viral spread. The first assay uses virus-like particles, or VLPs, which mimic the budding process. The second examines the protein-protein interaction between the specific elements of viral and host proteins involved in budding. And the third uses a nonlethal virus, vesicular stomatitis virus, to test the effectiveness of the viral inhibitors the team is screening.
In an experiment by the School of Veterinary Medicine’s Ronald Harty and Bruce Freedman, virus-like particles of Ebola (in green and yellow), which mimic the process by which the authentic Ebola virus spreads, exit a cell along filaments of actin (in red), a structural protein. Harty and Freedman are designing compounds to block this process, increasing the likelihood an infected individual could recover. (Photo: Gordon Ruthel)
“If all three of those look good,” says Harty, “then we know we have a good candidate to test with authentic Ebola virus.”
For those more-involved experiments, the Penn Vet team partners with colleagues at the U.S. Army Medical Research Institute of Infectious Disease, which has a Biosafety Level 4 laboratory.
Already, those tests have generated solid data, and now Harty and Freedman are working with colleagues within the Fox Chase Chemical Diversity Center to improve upon the viral inhibitors they’ve identified.
“We’re seeing good results with Ebola but also with related hemorrhagic fever viruses like Marburg and Lassa fever,” says Harty. “The next big step, and that’s what we’re working on now, is to try to tweak one of these inhibitors so we can use it in an animal model to see if it works there.”
Based on the promise of their findings to date, Harty and Freedman have launched a company, Intervir, to help refine and bring these inhibitors to market.
“The hope is that a therapeutic could be given to an individual who is positive for Ebola virus, to block the transmission or spread in that person or to dampen that spread and allow that person’s immune system more time to fight the virus,” says Harty. He likens such a drug to Tamiflu, which lessens the impact of the influenza in vulnerable individuals.
“We’re following the science,” adds Freedman, “and we’re learning a lot along the way. If we wind up with a drug that can help people, that will be something we’ll take to our graves as a life’s accomplishment.”