Scientists pivot to COVID-19 research
The COVID-19 pandemic sidelined scientists across the University of Florida, as labs closed and experimental research halted for several months. But some scientists in the College of Pharmacy saw an opportunity to pivot their existing research to join the fight against COVID-19.
“It was either stay at home and fight the disease like everyone else or use our expertise to contribute to society by trying to develop a new wave of antiviral drugs,” said Hendrik Luesch, Ph.D., a professor of medicinal chemistry and the Debbie and Sylvia DeSantis Chair in Natural Products Drug Discovery and Development in the UF College of Pharmacy.
Luesch and his research team in the Center for Natural Products, Drug Discovery and Development began screening their existing and unique compound libraries to identify natural products from novel marine organisms that could work against the virus. They identified several ways to attack SARS-CoV-2 — the virus that causes COVID-19 — at the level of infection, viral replication and downstream inflammation.
“We hypothesized that several of our compounds might be effective at these different levels and generated a focused, mechanism-based marine natural product library that we are screening against the virus within a nationwide network of COVID-19 researchers,” Luesch said. “We focused on compounds that do not act on the RNA-dependent RNA polymerase, but in a totally different, complementary fashion.”
Out of the first 20 selected candidates, Luesch’s team already identified two compounds that completely eradicated the virus in a cell culture through a novel mechanism. The compounds are now being analyzed in validation studies, as well as more mechanism and in vivo efficacy studies and are subject to medicinal chemistry campaigns.
Meanwhile, at the UF Research and Academic Center at Lake Nona, Jürgen Bulitta, Ph.D., a professor of pharmacotherapy and translational research in the UF College of Pharmacy, Ashley Brown, Ph.D., an associate professor in the UF College of Medicine and affiliated associate professor in the UF College of Pharmacy, and George Drusano, M.D., a professor in the UF College of Medicine, are leading research efforts to identify and optimize antiviral therapy against SARS-CoV-2.
The Lake Nona scientists are studying an existing class of antiviral drugs called Nucleoside Polymerase Inhibitors, or NUCS, which have shown broad spectrum antivirus activity. The three NUCS they identified for study include the intravenous therapy drugs galidesivir and remdesivir and the oral antiviral drug favipiravir.
“What makes these drugs special is that the parent compound is inactive and has to enter the cells to be converted within the cells into its active form,” Brown said. “There are several NUCS in development in vitro against a wide variety of viruses, and we found promising activity for several of them against other viruses in our prior work. We thought this would be the most promising place to start our research against SARS-CoV-2.”
Using translational antiviral pharmacology methods, human lung and colon cell lines were infected with the virus. After an hour of the virus attaching to the cells, it was washed away and replaced with varying concentrations of the drugs. Both galidesivir and remdesivir showed considerable activity at relatively low and clinically relevant concentrations, indicating the drugs’ potential in suppressing the virus. Remdesivir has further emerged as a COVID-19 treatment option, as the U.S. Food and Drug Administration issued an emergency use authorization in May. Meanwhile, favipiravir yielded some viral suppression but not at the same level as the other two drugs.
Identifying an effective antiviral therapy is only part one of the equation. The research team still needs to determine the optimal dose of the drug and how often it should be given to maximize viral suppression. Different modeling systems are being used to study the pharmacokinetic profile of the drugs, with the goal of predicting how the medicines will work in a patient population over time.
“We want to determine the dosing regimen that produces the fastest recovery and least toxicity for the patient,” said Bulitta, who also serves as the Perry A. Foote Eminent Scholar Chair in the UF College of Pharmacy. “Fortunately, UF has state-of-the-art technology and experts in experimental and mathematical modeling approaches here in Lake Nona. These capabilities enable us to come up with a scientifically sound and mechanistically informed dosage regimen in a very rapid basis to combat the crisis.”
Future clinical trials will be necessary for prospective validation. Brown, Bulitta and Drusano expect a clinically relevant dosage regimen for favipiravir to be available by fall. Work is already under way writing clinical protocols to support a clinical trial.
“It is really amazing how our research teams could come together and execute these drug studies in such a short time frame,” Bulitta said. “With Doctor Brown’s work on the antiviral efficacy studies, my team’s involvement in developing novel assays for intracellular concentration measurements and the combined effort of Dr. Drusano and myself working on the mathematical modeling, we’ve made it our collaborative mission to develop an effective therapy against SARS-CoV-2.”
Brown and Bulitta received a UF Clinical and Translational Science Institute, or CTSI, grant to support their research. The CTSI set up a $2 million pilot research fund for scientific teams with translational projects that could be rapidly mobilized during the pandemic.