A combination of remdesivir, a drug currently approved in the US for treating COVID-19 patients, and repurposed drugs for hepatitis C virus (HCV) was 10 times more effective at inhibiting SARS-CoV-2, the virus that causes COVID-19.
The combination therapy points a way toward a treatment for unvaccinated people who become infected, as well as for vaccinated people whose immunity has waned, for example due to the emergence of virus variants that escape this immune protection.
Four HCV drugs – simeprevir, vaniprevir, paritaprevir, and grazoprevir – in combination with remdesivir boosted the efficacy of remdesivir by as much as 10-fold, the researchers reported. The research team included scientists from Icahn School of Medicine at Mount Sinai, the University of Texas at Austin, and Rensselaer Polytechnic Institute (RPI).
Remdesivir targets a range of viruses and was originally developed over a decade ago to treat hepatitis C and a cold-like virus called respiratory syncytial virus (RSV). During the Ebola outbreak, remdesivir was tested in clinical trials and found to be safe and effective for patients. Early in the pandemic, it was seen as a good therapy for COVID-19 but did not live up to its early promise in studies.
The research team performed protein binding and viral replication studies on SARS-CoV-2, the virus that causes COVID-19, using remdesivir and 10 hepatitis C drugs, some of which are already approved by the US Food and Drug Administration.
RPI team had previously identified "striking similarity" between protease structures, or enzymes that are essential for coronaviral replication, in SARS-CoV-2 and HCV. The similarity raised the possibility that existing drugs which bind to and block the hepatitis C protease would have the same effect against SARS-CoV-2.
Using a supercomputer to model how drugs bind to viral proteins, the RPI researchers predicted that the 10 HCV drugs could bind snugly to the SARS-CoV-2 Main protease, named Mpro. In addition, they showed that seven of these drugs actually inhibited the SARS-CoV-2 protease. The research team at Icahn Mount Sinai then tested whether these seven drugs would inhibit SARS-CoV-2 virus replication in monkey and human cells grown in culture. In subsequent experiments the researchers were surprised to find that the four HCV drugs inhibited a different SARS-CoV-2 protease, known as PLpro. This observation proved to be very important. When each of the seven HCV drugs were tested in combination with remdesivir, only the four drugs that unexpectedly targeted PLpro boosted the efficacy of remdesivir, by as much as 10-fold.
Dr Adolfo Garcia-Sastre, one of the authors on the paper, Irene and Dr Arthur M Fishberg professor of medicine and director of the Global Health and Emerging Pathogens Institute at Icahn Mount Sinai, said: "Combined use of remdesivir with PLpro inhibitors for the treatment of COVID-19 could be a game changer for patients with COVID-19 who are not vaccinated. It could also reduce the possibility of selecting SARS-CoV-2-resistant viruses."
"The identification of PLpro as an antiviral target that has a synergistic effect in combination 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 to produce a highly effective antiviral cocktail that may potentially prevent the rise of resistance mutations," said Dr Kris White, assistant professor of microbiology at Icahn Mount Sinai.
"Because these HCV drugs are already approved for use and their potential side effects are known, such a combination therapy could be tested in humans more quickly than for a new drug," said Dr Robert M Krug, professor emeritus of molecular biosciences at The University of Texas at Austin and co-corresponding author of the paper.
One big drawback of remdesivir is that it must be administered intravenously, limiting its use to patients already admitted to the hospital. "Our goal is to develop a combination of oral drugs that can be administered to outpatients before they are sick enough to require hospitalisation," said Krug. "The HCV drugs that enhance remdesivir's antiviral activity are oral drugs. It is important to identify oral drugs that inhibit the SARS-CoV-2 polymerase in order to develop an effective outpatient treatment."
"Nearly 3m 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," said Dr Gaetano Montelione, a member of the Rensselaer Centre for Biotechnology and Interdisciplinary Studies (CBIS). "Here we see a promising synergy that, if confirmed through additional research and clinical trials, could provide a new antiviral to combat COVID-19."
Hepatitis C Virus Drugs That Inhibit the SARS-CoV-2 Papain-Like Protease Synergize with Remdesivir to Suppress Viral Replication in Cell Culture
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, Gaetano T. Montelione
Published in Cell Reports on 23 April 2021
Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We 3 assessed ten hepatitis C virus (HCV) protease-inhibitor drugs as potential SARS-CoV-2 4 antivirals. There is a striking structural similarity of the substrate binding clefts of SARSCoV-2 main protease (Mpro 5 ) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the Mpro 6 binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 Mpro 7 protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their Mpro 8 inhibiting activities did 9 not correlate with their antiviral activities. This conundrum was resolved by 10 demonstrating that four HCV protease inhibitor drugs, simeprevir, vaniprevir, paritaprevir, and grazoprevir inhibit the SARS CoV-2 papain-like protease (PLpro 11 ). HCV drugs that inhibit PLpro 12 synergize with the viral polymerase inhibitor remdesivir to inhibit 13 virus replication, increasing remdesivir’s antiviral activity as much as 10-fold, while those that only inhibit Mpro 14 do not synergize with remdesivir.