Health

Hepatitis C antivirals synergize with remdesivir to inhibit SARS-CoV-2 in vitro

In many countries, including the United States, the broad-spectrum antiviral drug remdesivir has been approved for treating coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen.

As the COVID-19 pandemic continues to spread globally, finding a targeted drug, or safe and effective drug combination, to combat SARS-CoV-2 infection remains a major objective of the scientific community.

Researchers at the University of Texas at Austin, Rensselaer Polytechnic Institute (RPI), and the Icahn School of Medicine at Mount Sinai in the USA have found that hepatitis C virus (HCV) protease-inhibitor drugs can inhibit SARS-CoV-2 and work effectively alongside remdesivir.

Their study, which was published in the journal Cell Reports, sheds light on the potential of drug combinations to stem viral transmission and treat patients with COVID-19. It also shows that four drugs used to treat hepatitis C synergize with remdesivir to make it up to ten times more effective at inhibiting SARS-CoV-2 in cell cultures.

Drug repurposing

Alongside mass vaccination and other prophylactic approaches, the effective control of the COVID-19 pandemic may also be dependent on targeted antivirals that help treat SARS-CoV-2 infection. Since there is an urgent need for effective therapeutics for severely ill COVID-19 patients, repurposing preapproved antiviral drugs for other viral pathogens could be an expedient avenue.

Since the start of the pandemic, scientists and health experts have searched for potential drugs to use in patients, especially those with moderate to severe COVID-19.

Remdesivir (or Veklury) was the first drug approved by the Food and Drug Administration (FDA) for treating COVID-19. For SARS-CoV-2 infection, it is indicated for hospitalized adults and children 12 years and older, who weigh at least 40 kg.

The drug is a broad-spectrum antiviral medication manufactured by Gilead Sciences. The nucleotide analog prodrug has never been used to treat any illness but was studied as a potential treatment for several diseases.

Initially produced as a potential treatment for hepatitis, in 2014 it was assessed as a possible treatment for the Ebola virus. Since then, the drug’s efficacy against other coronaviruses has been examined. Past studies have shown that remdesivir is effective in cell cultures and animal models against severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) – two viruses in the same subgenus (betacoronavirus) as SARS-CoV-2.

The study

The SARS-CoV-2 contains structural proteins, which can be targeted by antiviral therapeutics. For instance, the repurposed drug remdesivir inhibits the viral RNA-dependent polymerase, which facilitates the virus’s replication in host cells. Meanwhile, the HCV drugs target two other parts of SARS-CoV-2, called proteases.  These are also crucial for viral replication.

From there, the study researchers found similarities between the structures of HCV protease (NS3/4A) and SARS-CoV-2’s main protease (Mpro). They aimed to know if existing drugs bind to and inhibit an HCV protease and if these can be used for COVID-19.

The team used virtual docking experiments to model how drugs bind to viral proteins to arrive at the study findings. They predicted ten available HCV protease inhibitors could bind tightly to the Mpro binding cleft.

The team found that seven drugs inhibited SARS-CoV-2 Mpro protease activity and SARS-CoV-2 virus replication in cell cultures. The researchers noted that four HCV drugs – vaniprevir, simeprevir, grazoprevir, and paritaprevir – inhibited a new type of SARS-CoV-2 protease, known as papain-like protease.

The team also found that the four drugs synergize with remdesivir to inhibit viral replication, increasing the latter’s antiviral activity as much as ten-fold.

Hence, the study shows that a mixture of anti-hepatitis C drugs and remdesivir could potentially be an effective therapy avenue for COVID-19. Further research, namely in vivo pre-clinical trials, will be needed to corroborate the promising findings of this initial study and assess the regimen’s safety.

Our results indicate that the SARS-CoV-2 PLpro is an important target for future antiviral drug development that, when used in conjunction with polymerase inhibitors, could provide potent efficacy and protection from SARS-CoV-2, especially for virus variants that are resistant to vaccine generated antibodies,” the team concluded.

Finding effective drugs for COVID-19 is as crucial as ever. The number of cases skyrockets by the minute. To date, the total case toll has topped 149.90 million, while the deaths have reached 3.15 million.

The United States, India, and Brazil report the highest number of cases, reaching 32.61 million cases, 18.37 million cases, and 14.52 million cases, respectively.

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