There is a great benefit to repurposing drugs—screening drugs that are used in one application for a different application—especially when time is of the essence. A team of scientists at Scripps Research have focused on this idea, in an effort to find an effective antiviral drug against SARS-CoV-2. Calibr, the drug development division of Scripps Research, is leveraging a unique resource—the ReFRAME drug collection.
Calibr established the ReFRAME collection in 2018, with support from the Bill & Melinda Gates Foundation. The world’s leading collection of known drugs has since grown to comprise over 14,000 compounds, including drugs that are already being repurposed for a number of diseases, with new compounds being added every day. The drugs that are included in ReFRAME have been approved by the FDA for other diseases or have been extensively tested for human safety.
Drugs that are included in ReFRAME already have a lot known about them; safety, how well they may be tolerated, how to manufacture and synthesize them at scale. Therefore, they can be rapidly screened and advanced to the clinical setting, making the road from an early discovery to impacting patients much shorter. Calibr also developed an open-source database containing preclinical and clinical data on these compounds.
Previous studies showed that some of these molecules appear effective against related SARS and MERS coronaviruses. Now, the teams are working together to test those same compounds, and others, against the novel SARS-CoV-2 virus. These experiments, which test hundreds or thousands of compounds at a time, seek to identify drugs that prevent the virus from entering, infecting, or replicating in human cells.
Researchers are also screening for compounds that could be taken in combination with other drugs to improve the efficacy of antivirals such as remdesivir, a Gilead drug currently being tested in five COVID-19 clinical trials.
“The ReFRAME drug collection was put together to take all of the molecules that have been dosed safely in humans and make them available for screening to a variety of different collaborators both within the Scripps Research environment but also broadly, across the whole world, to be tested in a variety of different assays,” noted Arnab Chatterjee, PhD, vice president, medicinal chemistry, Calibr at Scripps Research.
ReFRAME goes international
Scripps Research has quickly established an international network of collaborating scientific laboratories to leverage ReFRAME. Chatterjee says the power of the ReFRAME drug collection is how it enables Calibr to quickly partner with leading research teams to develop precise and rapid screens against a wide range of diseases. “In the case of COVID-19,” he noted, “we can leverage this important resource, along with Calibr’s expertise in drug development and discovery, to collaborate with some of the world’s leading virology labs and quickly identify potential medicines.”
“COVID-19 is an unprecedented public health crisis that will only be brought fully under control by effective medical therapies,” said Peter Schultz, PhD, president and CEO of Scripps Research.”Repurposing drugs that have already been approved for use in humans, or compounds for which we have ample safety data, offers the most rapid path to finding an antiviral drug or drug combination that is effective against COVID-19.”
David Ho, MD, a virologist at Columbia University best known for his pioneering research on HIV therapies, said the ReFRAME collection helped his team to quickly pivot to searching for drugs that inhibit SARS-CoV-2. “The ReFRAME library was invaluable to allow us to screen through compounds that have been tested previously in humans,” Ho said. “It’s a fantastic resource for the scientific community.”
Soon after the initial COVID-19 outbreak began in China, Calibr began sharing the ReFRAME library and conducting joint experiments with other research teams at Scripps Research and collaborating institutions worldwide. Chatterjee noted that they sent off the first molecules to a coronavirus collaborating lab on January 24.
One of the earliest collaborations was established with Sumit Chanda, PhD, director of the immunity and pathogenesis program at Sanford Burnham Prebys Medical Discovery Institute, a neighbor of Scripps Research in La Jolla, CA. “Our lab is working around the clock to mine the ReFRAME collection,” said Chanda, “and we are hopeful that we have identified drug candidates that will be effective against COVID-19.”
Schultz said that while the results of the collaborations are still preliminary and need to be confirmed, they have already identified a number of compounds that show varying degrees of activity against the virus. The researchers hope to soon begin testing the drugs in cellular and animal models, including testing combinations of drugs that work by two different mechanisms for improved enhanced effectiveness.