The only FDA-approved antiviral drug for treating COVID-19 patients, remdesivir, is up to 10 times more effective when it is mixed with a repurposed hepatitis C drug. This effect has been observed with several hepatitis C drugs including simeprevir, grazoprevir, paritaprevir, and vaniprevir. All four appear to have the same remdesivir-boosting mechanism: inhibition of the SARS-CoV-2 papain-like protease (PLpro).
These findings come from a multi-center study led by Adolfo García-Sastre, Ph.D., Robert M. Krug, Ph.D., and Gaetano T. Montelione, Ph.D., scientists affiliated with the Icahn School of Medicine at Mount Sinai, the University of Texas (UT) at Austin, and Rensselaer Polytechnic Institute (RPI), respectively. Each of these scientists is listed as a corresponding author of a paper (“Hepatitis C Virus Drugs That Inhibit the SARS-CoV-2 Papain-Like Protease Synergize with Remdesivir to Suppress Viral Replication in Cell Culture”) published this week in Cell Reports.
According to the article, the three scientists and their colleagues tested 10 hepatitis C virus (HCV) protease-inhibitor drugs, some of which are already approved by the FDA, as potential SARS-CoV-2 antivirals. This work explored a possibility that had been raised earlier by RPI scientists. Specifically, they had identified a “striking similarity” between protease structures, or enzymes that are essential for coronaviral replication, in SARS-CoV-2 and HCV. The similarity suggested that existing drugs known to bind to and block the hepatitis C protease might 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.
“We show that seven HCV drugs inhibit both SARS-CoV-2 Mpro protease activity and SARS-CoV-2 virus replication in Vero and/or human cells,” the authors of the Cell Reports article wrote. “However, their Mpro inhibiting activities did not correlate with their antiviral activities. This conundrum was resolved by demonstrating that four HCV protease inhibitor drugs [simeprevir, vaniprevir, paritaprevir, and grazoprevir] inhibit the SARS CoV-2 papain-like protease (PLpro).”
The authors reported that in combination with HCV drugs that inhibit PLpro, remdesivir’s antiviral activity is increased by as much as 10-fold. This effect, the authors added, is due to synergy between the HCV drugs, which are inhibitors of the PLpro polymerase, and remdesivir, which is a viral RNA polymerase inhibitor. The authors also suggested that their work could lead to a combination antiviral therapy for COVID-19. This therapy could be especially helpful to unvaccinated people who become infected, and to vaccinated people who experience waning immunity.
Because these hepatitis 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. One big drawback with remdesivir, however, 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 hospitalization,” said Krug, who is professor emeritus of molecular biosciences at UT Austin. “The HCV drugs that enhance remdesivir’s antiviral activity are oral drugs. Ideally, we would need an oral drug that inhibits SARS-CoV-2 in the same way as remdesivir to develop an effective combination treatment.”
“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,” added Garcia-Sastre, who is the Irene and Dr. Arthur M. Fishberg professor of medicine and director of the Global Health and Emerging Pathogens Institute at Icahn Mount Sinai.
“Nearly three 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,” noted Montelione, who is a member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies. “Here we see a promising synergy that, if confirmed through additional research and clinical trials, could provide a new antiviral to combat COVID-19.”