Developing safe and effective therapeutics for a disease often takes years. However, the COVID-19 pandemic needs immediate therapeutics since already hundreds of millions of people have been infected and millions have died. Repurposing existing drugs that have already been approved for another disease has the potential to provide COVID-19 therapeutics more quickly.
This approach was taken for COVID-19 by an interinstitutional team of investigators: Professor Gaetano Montelione, Dr. Khushboo Bafna, Dr. Balasubramanian Harish, Dr. Theresa Ramelot, Dr. Thomas Acton, and Professor Catherine Royer at Rensselear Polytechnic Institute (RPI); Professor Kris White, Professor Adolfo Garcia-Sastre, Dr. Romel Rosales, Dr. Lisa Miorin, Elena Moreno, and Thomas Kehrer at Icahn School of Medicine at Mount Sinai; and Professor Robert Krug at the University of Texas at Austin.
These investigators tested ten available hepatitis C virus (HCV) drugs for their ability to suppress the replication of SARS-CoV-2, the virus that causes COVID-19, and showed that several of these HCV drugs have potential as therapeutics for COVID-19. In particular, four of these HCV drugs enhance the antiviral activity of remdesivir, the only approved antiviral drug for COVID-19, by as much as 10-fold. This study was published in the journal Cell Reports.
Professor Montelione, who is a corresponding author of the paper, said: “To provide antiviral drugs that can be rapidly deployed to combat the COVID-19 pandemic, we carried out the present study to identify currently available drugs that could potentially be repurposed as inhibitors of the SARS-CoV-2 virus that causes the COVID-19 disease.”
The motivation for this study was the observation by the RPI investigators that there is a striking similarity between the structures of the HCV protease and one of the SARS-CoV-2 proteases, called the Main protease. These viral proteases play essential roles in viral infection. They wondered whether existing drugs that bind to, and inhibit an HCV protease might also bind to, and inhibit this SARS-CoV-2 protease.
Using a supercomputer to model how drugs bind to viral proteins, the RPI researchers predicted that ten HCV drugs could bind snuggly to this SARS-CoV-2 protease. In addition, they showed that seven of these drugs inhibited this SARS-CoV-2 protease
The research team at Mount Sinai then tested these seven drugs in a secure biocontainment facility for their ability to inhibit SARS-CoV-2 virus replication in monkey and human cells grown in culture. All seven HCV drugs inhibited virus replication.
In subsequent experiments the researchers were surprised to find that four of the HCV drugs (simeprevir, vaniprevir, paritaprevir and grazoprevir) inhibited the other SARS-CoV-2 protease called the PLprotease. These results proved to be very important.
Remdesivir, the only approved antiviral drug for COVID-19, targets a protein of the SARS-CoV-2 coronavirus called the RNA polymerase which synthesizes viral RNAs. Because the two SARS-CoV-2 proteases are needed for the production of a functional RNA polymerase, the HCV drugs might be expected to enhance the efficacy of remdesivir in inhibiting virus replication. The investigators showed that only the four HCV drugs that target the unexpected SARS-CoV-2 PLprotease boost the efficacy of remdesivir, by as much as 10-fold. In contrast, the HCV drugs that target only the SARS-CoV-2 Main protease did not enhance the efficacy of remdesivir.
As stated in the paper: “HCV drugs that are strongly synergistic with remdesivir are most pertinent for the goal of the present study. Repurposed drugs may not have sufficient inhibitory activity on their own to achieve clinical efficacy. Synergy with remdesivir increases the potency of both the proposed repurposed HCV drugs and remdesivir.”
“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.
As Adolfo Garcia-Sastre emphasized, “Combined use of remdesivir with an inhibitor of
the PLprotease for the treatment of COVID-19 would also reduce the possibility of selecting SARS-CoV2 resistant viruses.”
The HCV drugs are administered orally, whereas remdesivir is administered intravenously. Consequently, treatment of COVID-19 patients with a combination of remdesivir with an HCV drug would have to take place in hospitals. The results of this paper strongly support setting up a clinical trial to test this drug combination on hospitalized patients.
In addition, as stated by Krug: “Our goal is to develop a combination of oral drugs that can be administered to outpatients before they are sick enough to require hospitalization. For this purpose, it is necessary to identify oral drugs that inhibit the SARS-CoV-2 polymerase in order to develop an effective outpatient treatment.”
Journal Reference and Main Image Credit:
Bafna, K., White, K., Harish, B., Rosales, R., Ramelot, T. A., Acton, T. B., Moreno, E., Kehrer, T., Miorin, L., Royer, C. A., García-Sastre, A., Krug, R. M., & Montelione, G. T. (2021). Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture. Cell reports, 35(7), 109133. https://doi.org/10.1016/j.celrep.2021.109133