In combination with drugs currently used to treat hepatitis C, the antiviral inhibdesivir is 10 times more effective in treating cells infected with SARS-CoV-2, the virus that causes COVID-19.
This finding, published this week in Cell Reports, from Gaetano Montelione, a professor of chemistry and chemical biology at Rensselaer Polytechnic Institute, and his associates at the Icahn School of Medicine at Mount Sinai and the University of Texas at Austin, boosts reuse the potential for available drugs as COVID-19 antivirals in cases where a vaccine is not practical or effective.
Remdesivir, which blocks viral replication by disrupting a viral polymerase, must be administered intravenously, with its use limited to patients ill enough to be hospitalized. However, the efficacy of the drug combination would extend to other polymerase inhibitors, at least one orally administered version of which is in development, allowing for an oral drug combination to be taken at home.
Worldwide, nearly 3 million people have died from COVID-19. There are situations when the vaccine is not the best option and it would be helpful to have orally available antivirals, ”said Montelione, a member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies (CBIS). “Here we see a promising synergy that, if confirmed by additional research and clinical trials, could provide a new antiviral agent to combat COVID-19.”
New-destination drugs, which have already been approved for use as therapeutics for another disease, may be able to be approved for clinical use more quickly than newly developed, more specific and potent drugs. Remdesivir itself is a recycled antiviral drug originally developed for the treatment of hepatitis C, Ebola virus disease and other viral infections.
“Recycled drugs can be quickly tested and approved for safe use, while more effective therapies are in development,” said Robert Krug, virologist and professor emeritus at the University of Texas at Austin, who helped initiate the collaboration, interprets the results, and write the paper.
The Cell Reports paper identifies four hepatitis C drugs, simeprevir, grazoprevir, paritaprevir, and vaniprevir, that showed a synergistic effect – an effect greater than the sum of its parts. For example, when administered at low doses to virus-infected cells in the presence of simeprevir, 10 times less remdesivir is required to inhibit 90% of the virus than when remdesivir is used alone. By increasing the efficacy of the polymerase inhibitor inhibdesivir, the required dosage is lowered and therefore may be more effective, and may also reduce unwanted side effects in the treatment of COVID-19.
The researchers discovered the synergistic effect as part of an effort to identify existing drugs that can be used against COVID-19. Remdesivir and the hepatitis C drugs inhibit viral replication, but they target different aspects of the process. The RNA that the virus injects into the cell causes it to make two polyproteins, which are then cut into more than two dozen smaller pieces that help the virus to replicate, and are excellent targets for antivirals that block their activity. Remdesivir targets a polymerase cluster, but many antivirals target viral proteases, enzymes necessary for the virus life cycle.
In previous work, Montelione, Krug and Khushboo Bafna, a postdoctoral researcher at Rensselaer, used a bioinformatics approach to identify existing proteins that resemble the protease structures of the coronavirus. The search identified a “striking resemblance” to a hepatitis C virus protease, which is the target of several approved drugs. This similarity between the structures of the main proteases of the two viruses raised the possibility that existing drugs that bind and block the hepatitis C protease might have the same effect on at least one of the proteases, called Mpro, in SARS-CoV -2. That possibility was confirmed by multiple consecutive studies, including Bafna’s docking simulations using supercomputer facilities at the Rensselaer Center for Computational Innovations, which predicted the effect of various hepatitis C drugs on the SARS-CoV-2 Mpro.
In Cell Reports, the team conducted protein binding and viral replication studies with the SARS-CoV-2 virus, remdesivir, and 10 hepatitis C drugs, some of which have already been approved by the Food and Drug Administration. Seven of the drugs, tested in a secure biocontainment facility on Mount Sinai, inhibit Mpro and suppress the replication of the SARS-CoV-2 virus. These studies were made possible by specialized expertise in the laboratories of research associates Adolfo García-Sastre and Kris White on Mount Sinai.
But careful analysis of the data revealed that three hepatitis C drugs acted not only on Mpro, but also on the second viral protease, the papain-like protease called PLpro. It is this activity that creates the synergy with the polymerase inhibitor inhibdesivir. These results indicate that PLpro is an important target for the future development of antiviral drugs, especially for virus variants resistant to vaccine-generated antibodies.
“The identification of PLpro as an antiviral target that has a synergistic effect with remdesivir is a very important finding. We hope that this work will encourage the development of specific SARS-CoV-2 PLpro inhibitors for inclusion in combination therapies with polymerase inhibitors to produce a highly effective antiviral cocktail that will also prevent the emergence of resistance mutations, ”said Kris White, a assistant professor. at Mount Sinai School of Medicine.
Adolfo García-Sastre, professor of virology at Mount Sinai, stressed, “Combined use of remdesivir with an inhibitor of the PLpro to treat COVID-19 would also reduce the ability to select SARS-CoV-2 resistant viruses.”
Reference: “Hepatitis C Virus Drugs That Inhibit the SARS-CoV-2 Papain-Like Protease 2 Synergize with Remdesivir to Suppress Viral Replication in Cell Culture” by Khushboo Bafna, Kris White, Balasubramanian Harish, Romel Rosales, Theresa A. Ramelot, Thomas B. Acton, Elena Moreno, Thomas Kehrer, Lisa Miorin, Catherine A. Royer, Adolfo García-Sastre, Robert M. Krug and Gaetano T. Montelione, April 26, 2021, Cell Reports.
DOI: 10.1016 / j.celrep.2021.109133
The studies at CBIS were conducted by Gaetano Montelione and Catherine Royer, professor of biological studies, along with postdoctoral fellows Bafna and Balasubramanian Harish. “These techniques and approaches made it possible to establish similarity between target molecules and accelerate discovery in a time of urgent need. The research is an excellent example of the broader benefits bioinformatics and interdisciplinary biotechnology can bring to human health, ”said Deepak Vashishth, director of CBIS.
“Hepatitis C virus drugs that inhibit the SARS-CoV-2 papain-like protease 2 synergize with Remdesivir to suppress viral replication in cell culture” was published in Cell Reports with support from the National Institutes of Health. At Rensselaer, Montelione was joined by Professor Catherine Royer, as well as Bafna, Harish, Theresa A. Ramelot and Thomas B. Acton. Adolfo García-Sastre and Kris White led the effort on Mount Sinai with Romel Rosales, Elena Moreno, Thomas Kehrer and Lisa Miorin. Robert M. Krug is a contributor from the University of Texas at Austin.