New Findings Suggest Hepatitis C Drugs May Multiply Effect of COVID-19 Antiviral Remdesivir

According to new research from Rensselaer Polytechnic Institute (RPI), the antiviral remdesivir is 10 times more effective in treating cells infected with SARS-CoV-2 when combined with drugs currently used to treat hepatitis C virus (HCV).

The finding raises the potential for repurposing available drugs as COVID-19 antivirals for cases in which a vaccine is not practical or effective, according to RPI chemistry and chemical professor Gaetano Montelione.

“Nearly 3 million people have died worldwide from COVID-19. There are situations where the vaccine isn’t the best option and it would be helpful to have orally available antivirals,” Montelione said in a press release. “Here we see a promising synergy that, if confirmed through additional research and clinical trials, could provide a new antiviral to combat COVID-19.”

Repurposed drugs that are already approved for use as therapeutics for a different disease could potentially be approved for clinical use more rapidly than newly developed, more specific, and potent drugs. Further, remdesivir itself is a repurposed antiviral drug, originally developed to treat HCV, Ebola, and other viral infections.

“Repurposed drugs have the potential to be tested and approved quickly for safe use, while more effective therapies are under development” said study co-author Robert Krug, virologist and professor emeritus at the University of Texas at Austin, who helped to initiate the collaboration, in a press release.

The Cell Reports paper identifies 4 HCV drugs, simeprevir, grazoprevir, paritaprevir, and vaniprevir, which all exhibit a synergistic effect. For example, when administered at low doses to virus-infected cells in the presence of simeprevir, 10 times less remdesivir is needed to inhibit 90% of the virus compared with remdesivir monotherapy, according to the study.

The researchers discovered the synergistic effect as part of an effort to identify existing drugs that could be used against COVID-19. Although remdesivir and the HCV drugs inhibit viral replication, they target different aspects of the process. The RNA that the virus injects into the cell causes it to make 2 polyproteins, which are then cut into more than 2 dozen smaller pieces that help to replicate the virus and make excellent targets for antivirals that block their activity, according to the study.

The researchers performed protein binding and viral replication studies with the SARS-CoV-2 virus, remdesivir, and 10 HCV drugs, with some being approved by the FDA. Seven of the drugs inhibit Mpro and suppress the replication of SARS-CoV-2, according to the study. Further analysis of the data revealed that 3 HCV drugs were acting not only on Mpro, but also on second viral protease, the papain-like protease, PLpro.

These results indicate that PLpro is an important target for future antiviral drug development, especially for virus variants that are resistant to vaccine-generated antibodies, according to the study authors.

“The identification of PLpro as an antiviral target that has a synergistic effect with remdesivir is a very important finding. We hope 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 rise of resistance mutations,” said Kris White, an assistant professor at Mount Sinai School of Medicine, in the press release.

REFERENCE

Hepatitis C drugs multiply effect of COVID-19 antiviral remdesivir. Rensselaer. Published April 27, 2021. Accessed April 29, 2021. https://news.rpi.edu/content/2021/04/27/hepatitis-c-drugs-multiply-effect-covid-19-antiviral-remdesivir