Every tree was once an acorn. With time and care, acorns grow into branching trees. The same can be said of science – an idea germinates and grows into something that reaches out of the lab to help people.
This is the idea behind Quercus Molecular Design (QMD), which takes its name from the Latin word for oak tree. QMD develops broad-spectrum antiviral drugs with indications ranging from herpes viruses to SARS-CoV2, the pathogen responsible for COVID-19.
Sandra Weller, QMD’s chief biology officer and Board of Trustees Distinguished professor of molecular biology and biophysics in UConn’s School of Medicine, has been studying the mechanism of replication of human herpes viruses for more than 40 years.
Weller paired her in-depth understanding of the molecular mechanisms of viral replication with the expertise of Dennis Wright, a professor of medicinal chemistry in the UConn School of Pharmacy and QMD’s chief chemistry officer. Wright’s lab develops chemical compounds that target and block specific proteins in pathogens from performing their function, thus preventing the pathogen from growing.
The nine human herpesviruses are among the most widespread infectious pathogens in the world, with 90% of the population infected with three or more different herpesviruses. Herpesviruses cause latent infection, meaning once someone is infected, the virus stays in the body forever and can be reactivated. Usually, this reactivation does not cause severe symptoms, but for immunocompromised people it can be life-threatening and is a major problem in transplant and oncology patients.
While there are effective treatments for some kinds of herpesviruses, the approved drugs can be toxic or face problems of drug-resistance.
Wright, who had previously focused on developing treatments for antibiotic-resistant bacteria, saw the transition to viral research as an exciting new challenge.
“It was a pretty natural fit from within that realm of infectious diseases to move from bacteria to viral pathogens, which was very exciting and challenging,” Wright says.
This collaboration between the Weller and Wright labs demonstrates the importance of interdisciplinary teams for leveraging basic research discoveries into potential therapeutics.
“I’ve always been interested in bringing researchers together so one person’s expertise can complement another person’s expertise,” Weller says. “It makes the work so much more powerful.”
QMD is focused on creating inhibitors of viral nucleases, enzymes essential for viral genome replication, making them attractive therapeutic targets.
This is the first time scientists are looking at inhibiting this enzyme.
QMD has tested their inhibitors on the four most clinically relevant of the nine herpes viruses and, so far, it is effective against all of them. Weller says it is very likely effective against all nine since the herpes nuclease is highly conserved across all herpesviruses. The team is now in the process of testing the treatment in animal models.
A Game of Odds
These developments couldn’t come at a more critical time. In early 2020 the world was shaken by the emergence of a novel coronavirus responsible for the COVID-19 pandemic.
When information about the structure of the coronavirus came out, Weller and Wright immediately recognized that it had a remarkably similar nuclease protein to the one they had been working with for years.
“We were excited that the coronavirus makes a proofreading nuclease that is structurally related to the nuclease we already work on,” Weller says.
They quickly mobilized to apply their work to the coronavirus, collaborating with Dr. Mark Denison at Vanderbilt University, where they are authorized to work directly with the virus. In addition to the potential for the nuclease to serve as a drug target, the team was intrigued by the possible synergy with the only current coronavirus drug, Remdesivir.
Remdesivir is a fake RNA building block that the virus mistakenly incorporates into its genome, creating mutations that kill the virus. This drug could be combined with QMD’s nuclease inhibitors, shutting down the proofreader mechanism and enhancing the impact of Remdesivir.
It’s important to remember that drug resistance is a game of odds, says Wright. If treatment inhibits one enzyme, the virus can mutate to become resistant to that inhibition method. However, if multiple treatments targeting different viral enzymes are combined, resistance becomes much less likely.
This strategy has been successfully applied to HIV treatment for years using a drug “cocktail” which inhibits multiple parts of the virus.
“That taught us a lot about how we should be thinking about combination therapy,” Weller says.
Starting Up
With the help of UConn technology commercialization and entrepreneurship programs, the pair formally founded QMD in 2015.
“Once we started collaborating on the development of therapeutics, it made sense to think about creating a startup company,” Weller says. “We were fortunate to have support from the University to help us advance our technologies and our business.”
QMD joined UConn’s Technology Incubation Program (TIP) in 2017, gaining access to additional lab space, business support services, and mentorship from the experts in UConn’s Technology Commercialization Services group.
“UConn’s incubator has provided a very encouraging environment,” Weller says. “We’re scientists running a business. Running a business requires a very different set of skills.”
TIP helps startups launch and grow their businesses by pairing them with UConn’s world-class facilities and resources and connecting them to a vast network of experienced investors and entrepreneurs across industry sectors.
“You can make these discoveries within basic research and you can protect that intellectual property, but it isn’t always easy to find a path to create a commercially viable product,” Wright says.
Getting Ahead of the Curve
QMD hopes to work with public investors on the state and federal level to develop a product with widespread public health ramifications. It can be difficult to attract private investors as, by the nature of infectious disease drug development, it is a risky endeavor with uncertain payoff.
In addition to treating existing viruses, the development of this kind of drug could help treat future viral outbreaks. The COVID-19 pandemic is actually the third zoonotic coronavirus that has jumped into humans in the past two decades, and the likelihood of another is high.
Developing a successful antiviral could help public agencies be prepared for another pandemic by providing an important bridge to a vaccine.
“We hope going forward there will be more synchronized interactions between the public and private sectors,” Wright says.
