Extensive Study Identifies Over a Dozen Existing Drugs As Potential Treatments for COVID-19

A researcher at Calibr, the drug discovery division of Scripps Research, who works in the high-throughput screening facility used to identify potential COVID-19 therapies. Credit: Scripps Research

FDA-approved drugs or experimental drugs with sufficient health data can quickly be tested in humans as COVID-19 therapies.

In mining the world’s most comprehensive drug reuse collection for COVID-19 therapies, scientists have identified 90 existing drugs or drug candidates with antiviral activity against the coronavirus causing the ongoing global pandemic.

Among those compounds, the Scripps Research study identified four clinically approved drugs and nine compounds in other stages of development with strong potential for reuse as oral drugs for COVID-19, according to results published today (June 3, 2021) in the journal Nature. have been published Communication.

Of the drugs that prevented the coronavirus from replicating in human cells, 19 were found to interact with or boost its activity with remdesivir, an antiviral therapy approved to treat COVID-19.

“While we now have effective vaccines against COVID-19, we are still missing highly effective antiviral drugs that can prevent or prevent COVID-19 infections from worsening,” said Peter Schultz, PhD, president and CEO of Scripps Research.

“Our results raise the possibility of some promising ways to reuse existing oral medications with efficacy against SARS-CoV-2,” he adds. “We have identified promising existing drugs and are also leveraging our findings to develop optimized antivirals that will be more effective against SARS-CoV-2, including variants and drug-resistant strains, as well as against other coronaviruses that currently exist or may be in the future. could appear. .”

In a collaboration between Calibr, the drug discovery division of Scripps Research, and a team of researchers from the institute’s Division of Immunology and Microbiology, the study tested more than 12,000 drugs in two different types of human cells infected with SARS-CoV. 2.

The drugs used in the study came from the ReFRAME drug reuse library, which was established by Calibr in 2018 with support from the Bill & Melinda Gates Foundation to address areas of urgent unmet medical need, especially neglected tropical diseases. The collection includes FDA-approved drugs and other experimental compounds that have been tested for safety in humans.

“Early on in the COVID-19 pandemic, we saw that ReFRAME could be used to screen for hits against SARS-CoV-2,” said Arnab Chatterjee, PhD, vice president of medicinal chemistry at Calibr. “In the months that followed, we launched many scientific collaborations to accelerate drug discovery, both internally at Scripps Research and with partners at home and abroad.”

In the Scripps Research study, the scientists treated two different types of laboratory-grown SARS-CoV-2 infected human cells with each of ReFRAME’s 12,000 drugs. After 24 or 48 hours, they measured the level of viral infection in the cells to determine whether the drugs prevented the virus from multiplying. In some cases, they applied two drugs at once to see if the compounds would work together against the virus.

“Some of the most effective antiviral strategies are ‘cocktails’ in which patients are given various drugs to fight the infection, such as those used to treat HIV infections,” says the study’s corresponding author, Thomas Rogers, MD, PhD, an adjunct assistant professor in the Department of Immunology and Microbiology at Scripps Research and assistant professor of medicine at UC San Diego.

Of the thousands of drugs screened, the researchers identified a total of 90 compounds that prevented SARS-CoV-2 from replicating in at least one of the human cell lines. Of these, 13 had the greatest potential for reuse as COVID-19 therapies, based on their potency, cell-line-independent activity or likely mechanism of action, pharmacokinetic properties and human safety profiles.

Four of the drugs — halofantrine, nelfinavir, simeprevir and manidipine — have already been approved by the FDA, and nine others are in various stages of the drug’s development process.

From the drug combination screens, the researchers found 19 drugs that had an additive effect when administered with remdesivir, the antiviral drug produced by the pharmaceutical company Gilead and approved by the FDA for use in patients diagnosed with COVID-19. . An additive effect means that the drugs were both active against the virus when applied together.

“The potential benefit of a therapeutic strategy that uses a combination of drugs is that taking a lower dose of a drug can reduce the risk of side effects from that drug,” said Malina Bakowski, PhD, the lead author of the Nature Communications study. document and principal investigator at Calibr.

Two additional drugs went a step further and had a synergistic effect on remdesivir, meaning the drugs increase remdesivir’s ability to suppress the virus. These two drugs were riboprine, a compound that has been tested as a preventative against nausea and surgical infections, and 10-deazaaminopterin, a derivative of the vitamin folic acid.

Based on the results of cell culture screening, the researchers tested the best performing drug candidates in human tissue cells and an animal model to determine which are most likely to work in human patients. Building on their success in identifying potential COVID-19 therapies, the Scripps Research team continues to advance other promising candidates through their drug discovery pipeline.

“The results of the cellular testing and animal models are promising and the need for medical remedies to address COVID-19 remains urgent,” said Schultz. “It is critical that we take great care to determine what is safe and effective, as diligence is the most appropriate avenue to find new therapies that will make a difference to patients.”

Results of the ReFRAME library screen are available on the data portal reframedb.org.

Reference: “Drug repurposing screens identify chemical entities for the development of COVID-19 interventions” June 3, 2021, Nature Medicine.
DOI: 10.1038/s41467-021-23328-0

“Drug repurposing screens identify chemical entities for the development of COVID-19 interventions” was co-authored by Malina Bakowski, Nathan Beutler, Karen Wolff, Melanie Kirkpatrick, Emily Chen, Tu-Trinh H. Nguyen, Laura Riva, Namir Shaabani, Mara Parren, James Ricketts, Anil Gupta, Kastin Pan, Peiting Kuo, MacKenzie Fuller, Elijah Garcia, John Teijaro, Linlin Yang, Debashis Sahoo, Victor Chi, Edward Huang, Natalia Vargas, Amanda Roberts, Soumita Das, Pradipta Ghosh, Ashley Woods , Sean Joseph , Mitchell Hull, Peter Schultz, Dennis Burton, Arnab Chatterjee, Case McNamara and Thomas Rogers. The research was funded by the Bill & Melinda Gates Foundation, the National Institutes of Health and the Sanford Stem Cell Clinical Center at UC San Diego Health.