As many labs go quiet, research to find a coronavirus therapy ramps up
Virologists Susan Weiss, Sara Cherry, and others at the Perelman School of Medicine are collaborating to inform the search for therapies against SARS-CoV-2.
Researchers at Penn are using high-throughput screening to test thousands of compounds—both those that are FDA approved and those that are not—to see if they can put a dent in the activity of the SARS-CoV-2 virus, which causes COVID-19.
The coronavirus that launched a worldwide pandemic is new to science, but that doesn’t mean scientists are starting from scratch to study it. Expertise from years—in some cases, decades—of work is being leveraged to address the novel threat posed by SARS-CoV-2. While Penn scientists working on other projects have largely had to put their labs into maintenance mode to enact the social distancing required by the disease’s spread, studies of coronavirus are kicking into high gear.
Susan Weiss, a virologist at Penn Medicine, has been studying coronaviruses for four decades, and is using her expertise to contribute to efforts to attack the emerging threat. (Image: Weiss laboratory)
For virologist Susan Weiss of the Perelman School of Medicine, coronaviruses have been a consistent focus of her four-decade-long career. Her studies have used mouse coronavirus models to investigate the basic biology of the virus, as well as the ways in which it interacts with and exploits the immune system of the animals it infects. She has also devoted significant attention to the pathogenesis of the human MERS-CoV.
“We’ve learned an enormous amount about how the virus interacts with its hosts,” says Weiss. “If I can make a plug for basic science, I will say that the more we know about a virus like this before it hits us, the better prepared we’ll be when it comes along.”
The importance of those efforts are now clear, with the practical concern of how to beat this virus top of mind.
Specialized personal protective gear ensure scientists like Yize (Henry) Li, a research associate in Weiss’s lab, can safely work with the virus in the Biosafety Level-3 laboratory. (Image: Weiss laboratory)
The first studies, says Weiss, “are very mundane and simple.” They’ll be assessing quantities of virus in samples to determine how they might inactivate it sufficiently to safely study it outside the BSL-3 lab. And as they obtain more samples, they’ll be isolating and sequencing them, looking at variations among them to see how the virus is evolving. The work in the BSL-3 lab may also help researchers at Penn Medicine and the School of Engineering and Applied Science who are leading work to develop a rapid test for the virus. Yize (Henry) Li, a research associate, along with several others in her group are spending many hours in the BSL-3 lab devoted to this effort.
Sara Cherry of Penn Medicine is applying her expertise in high-throughput screening to work against SARS-CoV-2. (Image: Eric Sucar)
In parallel, the lab of virologist Sara Cherry, who has extensive expertise in screening potential therapeutics for their effectiveness against pathogens, particularly insect-borne viruses such as West Nile, Chikungunya, and Zika, has been gearing up to screen against the new coronavirus. She obtained the virus from Weiss, and is expanding it rapidly.
“We have a number of small molecule libraries we’re going to start screening, with a goal of finding therapeutics that are active against this virus, as well as combinations of therapies that may be even more active,” says Cherry.
Microbiologist Holly Ramage is among those working in the Biosafety Level-3 lab at Penn Medicine to screen potential antivirals against the novel coronavirus. (Image: Penn Medicine)
About 1,500 of these compounds are already FDA-approved for use in humans, including drugs like chloroquine—a malaria prophylactic—and remdesivir—a drug originally developed to treat Ebola that proved relatively ineffective against that disease but may hold greater promise for SARS-CoV2.
“These are two drugs that are currently being tested in clinical trials,” Cherry says. “So if those are successful at combating the virus it would be fairly quick to get them to patients.”
Cherry and Holly Ramage, a research assistant professor at Penn Medicine, are working in the BSL-3, as well as the school’s High-throughput Screening Core along with members of the Cherry lab to rapidly screen thousands of compounds. These include large numbers that are approved, along with many others that aren’t yet approved for human use.
Educated guesses
Insights from researchers such as Weiss who have spent years elucidating aspects of coronavirus biology provide important clues about finding the virus’s weak spot.
Genetically speaking, coronaviruses are relatively sophisticated. They possess the largest RNA genome of any virus, suggesting they have the raw material to make a wide assortment of proteins with which they can infect and hijack a host’s cells, and manipulate and evade the immune system. But antiviral drugs have focused on a handful of key proteins.
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One is ubiquitous across RNA viruses, the RNA polymerase. Viruses use this enzyme to generate more copies of its RNA, enabling it to replicate inside the host. Some drugs try to shut down the virus’s life cycle by attempting to fool the virus into making mistakes in replicating its RNA. These nucleoside analogs, of which redemsivir is one, cause the virus to substitute the wrong “letter” into their RNA sequence, causing their RNA strand to break—resulting in a dead end for the virus. Cherry will be screening thousands of nucleoside analogs to potentially discover more potent drugs.
Other potential therapies target the virus at an early stage of its life cycle, preventing virus entry into cells—a process that is also the focus of many vaccine development efforts. (More to come on that in an upcoming Penn Today story.) Chloroquine, for example, and a related compound hydroxychloroquine, modify characteristics of compartments in the host’s cell membranes to make it more difficult for the virus to enter.
Still other studies rapidly coming online suggest that the novel coronavirus may be sensitive to interferon, a drug commonly given to treat cancer. Yet Weiss and Cherry note that there are nuances to how each of these may be effective against the virus that we won’t understand until more studies are completed.
The best of Penn
Overall, Weiss and Cherry note that the crisis has sparked incredible creativity and collaboration across the University and the scientific community as a whole. Last week, the Penn Medicine Department of Microbiology launched the new Center for Research on Coronavirus and Other Emerging Pathogens to centralize and funnel support for pandemic-related work.
“The Center is a place where we can gather everything and everyone together to try to encourage collaborations, fundraise, share information, and really encourage every aspect of attacking this virus—and any future ones,” says Weiss, who is codirecting the new Center with departmental colleague Frederic Bushman.
To accelerate progress against SARS-CoV-2, the faculty actively studying the virus are soliciting ideas for how to proceed from researchers across the University community, many of whom have been sidelined as their own research goes on ice for the time being.
“Ultimately we hope to leverage all this expertise we have at Penn to identify some strategies we wouldn’t have thought about before,” says Cherry. “There’s a lot of people out there who want to help.”
For the Penn scientists, studies of the novel coronavirus are only getting started. Weiss is collaborating with researchers at Colorado State University to study the immune response to SARS-CoV-2 infection in bats—the animal in which it is believed the virus originated. Cherry hopes to learn more about which proteins the virus relies on for infection and what cell types are most affected.
“We’re trying to work across the basic as well as the clinical sciences to see if we can make an impact here,” says Cherry. “I hope we can.”
Homepage image: Under a scanning electron microscope, SARS-CoV-2 (in yellow), the virus that causes COVID-19, emerges from the surface of cells (in blue/pink). (Image: NIAID-RML/NIH)
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