A combination of remdesivir, a drug currently approved in the United States for the treatment of patients with COVID-19, and reused drugs for hepatitis C virus (HCV) was 10 times more effective at inhibiting SARS-CoV -2, the virus responsible for COVID-19.
Combination therapy paves the way for treatment for unvaccinated people who are infected, as well as for vaccinated people whose immunity has weakened, for example due to the emergence of viral variants that escape this immune protection.
Four anti-HCV drugs – simeprevir, vaniprevir, paritaprevir and grazoprevir – in combination with remdesivir increased the effectiveness of remdesivir 10-fold, researchers reported today in Cell reports. The research team included scientists from the Icahn School of Medicine at Mount Sinai, the University of Texas at Austin, and the 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. At the start of the pandemic, it was seen as good therapy for COVID-19 but failed to deliver on its initial promises in studies.
The research team performed protein binding and viral replication studies on SARS-CoV-2, the virus responsible for COVID-19, using remdesivir and 10 hepatitis C drugs, some of which are already approved by the Food and Drug Administration.
The RPI team had previously identified a “striking similarity” between the protease structures, or enzymes essential for coronaviral replication, in SARS-CoV-2 and HCV. The similarity raised the possibility that existing drugs that bind to and block hepatitis C protease would have the same effect against SARS-CoV-2.
Using a supercomputer to model how drugs bind to viral proteins, RPI researchers predicted that the 10 anti-HCV drugs could bind tightly to the main protease in SARS-CoV-2, called Mpro. In addition, they showed that seven of these drugs actually inhibited the SARS-CoV-2 protease. Icahn Mount Sinai’s research team then tested whether these seven drugs would inhibit the replication of the SARS-CoV-2 virus in monkeys and cultured human cells. In later experiments, the researchers were surprised to find that the four anti-HCV drugs inhibited a different SARS-CoV-2 protease, known as PLpro. This observation turned out to be very important. When each of the seven anti-HCV drugs was tested in combination with remdesivir, only the four drugs that unexpectedly targeted PLpro increased the effectiveness of remdesivir 10-fold.
Adolfo Garcia-Sastre, PhD, one of the authors of the article, Irene and Dr Arthur M. Fishberg Professor of Medicine. and director of the Global Health and Emerging Pathogens Institute at Icahn Mount Sinai, said: “The combined use of remdesivir with PLpro inhibitors for the treatment of COVID-19 could be a game-changer for patients with COVID-19 who do not are not vaccinated. also reduce the possibility of selecting viruses resistant to SARS-CoV-2. “
“The identification of PLpro as an antiviral target which 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 to be included in combination therapies to produce an effective antiviral cocktail that can potentially prevent the rise of resistance mutations, ”said Kris White, PhD, assistant professor of microbiology at Icahn Mount Sinai.
“Since these HCV drugs are already approved for use and their potential side effects are known, such a combination therapy could be tested in humans faster than for a new drug,” said Robert M. Krug , PhD, Emeritus Professor of Molecular Biosciences at The University of Texas at Austin and corresponding co-author of the article.
A big disadvantage of remdesivir is that it has to be given intravenously, limiting its use to patients already admitted to hospital. “Our goal is to develop a combination of oral drugs that can be given to ambulatory patients before they are sick enough to require hospitalization,” Krug said. “Anti-HCV drugs that enhance the antiviral activity of remdesivir are oral drugs. It is important to identify oral drugs that inhibit SARS-CoV-2 polymerase in order to develop effective outpatient treatment.”
“Almost 3 million people have died worldwide from COVID-19. There are situations where the vaccine is not the best option and it would be helpful to have antivirals available orally,” Gaetano Montelione said. , PhD, member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies (CBIS). “Here we see a promising synergy which, if confirmed by further research and clinical trials, could provide a new antiviral to fight COVID-19.”
Other participants in this research are Catherine Royer, Theresa A. Ramelot, Thomas B. Acton and Balasubramanian Harish at RPI; and Romel Rosales, Elena Moreno, Thomas Kehrer and Lisa Miorin at Icahn Mount Sinai.
This research was supported by the National Institutes of Health, the RPI Center for Computational Innovations, the National Institute of Allergy and Infectious Diseases, the Defense Advanced Research Projects Agency, the Department of Defense, the JPB Foundation and the Open Philanthropy Project. .